Crystalline compounds

ABSTRACT

The present invention relates to crystalline forms of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride and compositions comprising the same and methods of making and using the same.

This application is a continuation of U.S. patent application Ser. No.15/820,241 filed Nov. 21, 2017 (now U.S. Pat. No. 10,280,141), which isa continuation of U.S. patent application Ser. No. 15/611,580 filed Jun.1, 2017 (now U.S. Pat. No. 9,856,217), which is a continuation of U.S.patent application Ser. No. 15/186,415 filed Jun. 17, 2016 (now U.S.Pat. No. 9,708,261), which claims priority to U.S. ProvisionalApplication No. 62/181,174 filed Jun. 17, 2015, the contents of each ofwhich are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to crystalline forms of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride andcompositions comprising the same and methods of making and using thesame.

BACKGROUND OF THE INVENTION

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, is a compound usefulas an unbalanced triple reuptake inhibitor (TRI), most potent towardsnorepinephrine reuptake (NE), one-sixth as potent towards dopaminereuptake (DA), and one-fourteenth as much towards serotonin reuptake(5-HT). This compound and its utility are disclosed in more detail inU.S. Patent Publication No. 2007/0082940, the contents of which arehereby incorporated by reference in their entirety.

Active pharmaceutical ingredients can exist in different physical forms(e.g., liquid or solid in different crystalline, amorphous, hydrate, orsolvate forms), which can vary the processability, stability,solubility, bioavailability, pharmacokinetics (absorption, distribution,metabolism, excretion, or the like), and/or bioequivalency of the activepharmaceutical ingredient and pharmaceutical compositions comprising it.Whether a compound will exist in a particular polymorph form isunpredictable. It is important in pharmaceutical development to generateand identify advantageous physical forms (e.g., free base or salt insolid, liquid, crystalline, hydrate, solvate, or amorphous forms) ofactive pharmaceutical ingredients. Therefore, there remains a need forparticular polymorph forms of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane.

SUMMARY OF THE INVENTION

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (“the Compound”) isshown as Formula I below:

The inventors have found particular polymorphs of the Compound inhydrochloric acid addition salt form. These particular polymorphs havedifferent stability and dissolution profiles and are especiallyadvantageous in the preparation of galenic formulations of various anddiverse kind, especially Crystalline Form A as described below.Therefore, in the first aspect, the invention provides crystalline formsof (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride,e.g.:

-   -   1.1 Crystalline Form A of the Compound in hydrochloric acid        addition salt form        ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride) (“Crystalline Form A”).    -   1.2 Formula 1.1 wherein the Crystalline Form A belongs to the        P2₁2₁2₁ space group and has the following unit cell parameters:        -   a=5.7779(2) Å, b=8.6633(2) Å, c=25.7280(8) Å, α=β=γ=90°.    -   1.3 Formula 1.1 wherein the Crystalline Form A belongs to the        P2₁2₁2₁ space group and has any combination of the following        unit cell parameters:        -   a=5-7 Å, e.g., 6 Å, e.g., 5.6-5.9 Å, e.g., 5.7-5.8 Å, e.g.,            5.8 Å, e.g., 5.78, e.g., 5.778 Å;        -   b=8-10 Å, e.g., 9 Å, e.g., 8.5-8.8 Å, e.g., 8.6-8.7 Å, e.g.,            8.7 Å, e.g., 8.66 Å, e.g., 8.663 Å;        -   c=25-27 Å, e.g., 26 Å, e.g., 25.6-25.9 Å, e.g., 25.7-25.8 Å,            e.g., 25.7-25.8 Å, e.g., 25.73 Å, e.g., 25.728 Å; and        -   α=γ=γ=90°.    -   1.4 Any of formulae 1.1-1.3 wherein the Crystalline Form A has a        calculated volume of V=1287.83(7) Å³.    -   1.5 Any of formulae 1.1-1.4 wherein the crystal structure of the        Crystalline Form A is obtained with a crystal having approximate        dimensions of 0.38 mm×0.30 mm×0.18 mm, e.g., a colorless plate        having approximate dimensions of 0.38 mm×0.30 mm×0.18 mm.    -   1.6 Any of formulae 1.1-1.5 wherein the crystal structure of the        Crystalline Form A is obtained with Mo Kα radiation, e.g., Mo Kα        radiation having λ=0.71073 Å.    -   1.7 Any of formulae 1.1-1.6 wherein the crystal structure of the        Crystalline Form A is obtained at 150 K.    -   1.8 Any of formulae 1.1-1.7 wherein the Crystalline Form A has a        single crystal structure represented by the ORTEP drawing of        FIG. 18.    -   1.9 Any of formulae 1.1-1.8 wherein the Crystalline Form A has a        calculated XRPD pattern as show in FIG. 23.    -   1.10 Any of formulae 1.1-1.9 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, 2-theta (°) values selected from the group        consisting of 15.4, 16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9,        and 25.7, wherein the XRPD is measured using an incident beam of        Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.11 Any of formulae 1.1-1.10 wherein the Crystalline Form A        exhibits an XRPD pattern comprising 2-theta (°) values of 15.4,        16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9, and 25.7, wherein the        XRPD is measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.12 Any of formulae 1.1-1.11 wherein the Crystalline Form A        exhibits an XRPD pattern having characteristic 2-theta (°)        values of 15.4, 16.6, 17.2, 18.5, 19.5, 20.5, 20.7, 22.9, and        25.7, wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.13 Any of formulae 1.1-1.12 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, 2-theta (°) values selected from the group        consisting 15.42, 16.55, 17.15, 18.50, 19.45, 20.46, 20.68,        22.90, and 25.69, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.14 Any of formulae 1.1-1.13 wherein the Crystalline Form A        exhibits an XRPD pattern comprising 2-theta (°) values of 15.42,        16.55, 17.15, 18.50, 19.45, 20.46, 20.68, 22.90, and 25.69,        wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation.    -   1.15 Any of formulae 1.1-1.14 wherein the Crystalline Form A        exhibits an XRPD pattern having characteristic 2-theta (°)        values of 15.42, 16.55, 17.15, 18.50, 19.45, 20.46, 20.68,        22.90, and 25.69, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.16 Any of formulae 1.1-1.15 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, 2-theta (°) values selected from those set forth in        Table A below:

TABLE A °2θ d space (Å) Intensity (%) 15.42 ± 0.20 5.741 ± 0.074 2616.55 ± 0.20 5.352 ± 0.064 40 17.15 ± 0.20 5.167 ± 0.060 29 18.50 ± 0.204.792 ± 0.051 100 19.45 ± 0.20 4.560 ± 0.046 38 20.46 ± 0.20 4.338 ±0.042 43 20.68 ± 0.20 4.291 ± 0.041 80 22.90 ± 0.20 3.880 ± 0.033 2225.69 ± 0.20 3.466 ± 0.027 70

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.17 Any of formulae 1.1-1.16 wherein the Crystalline Form A        exhibits an XRPD pattern comprising the 2-theta (°) values set        forth in Table A of formula 1.16, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.18 Any of formulae 1.1-1.17 wherein the Crystalline Form A        exhibits an XRPD pattern having characteristic 2-theta (°)        values as set forth in Table A of formula 1.16, wherein the XRPD        is measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.19 Any of formulae 1.1-1.18 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g. at least ten, 2-theta (0) values selected from        the group consisting of 12.3, 13.8, 15.4, 16.6, 17.2, 18.2,        18.5, 19.5, 20.5, 20.7, 22.9, and 25.7, wherein the XRPD is        measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.20 Any of formulae 1.1-1.19 wherein the Crystalline Form A        exhibits an XRPD pattern comprising 2-theta (°) values of 12.3,        13.8, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.5, 20.7, 22.9, and        25.7, wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.21 Any of formulae 1.1-1.20 wherein the Crystalline Form A        exhibits an XRPD pattern having representative 2-theta (°)        values of 12.3, 13.8, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.5,        20.7, 22.9, and 25.7, wherein the XRPD is measured using an        incident beam of Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.22 Any of formulae 1.1-1.21 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g. at least ten, 2-theta (0) values selected from        the group consisting of 12.26, 13.78, 15.42, 16.55, 17.15,        18.19, 18.50, 19.45, 20.46, 20.68, 22.90, and 25.69, wherein the        XRPD is measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.23 Any of formulae 1.1-1.22 wherein the Crystalline Form A        exhibits an XRPD pattern comprising 2-theta (°) values of 12.26,        13.78, 15.42, 16.55, 17.15, 18.19, 18.50, 19.45, 20.46, 20.68,        22.90, and 25.69, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.24 Any of formulae 1.1-1.23 wherein the Crystalline Form A        exhibits an XRPD pattern having representative 2-theta (°)        values of 12.26, 13.78, 15.42, 16.55, 17.15, 18.19, 18.50,        19.45, 20.46, 20.68, 22.90, and 25.69, wherein the XRPD is        measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.25 Any of formulae 1.1-1.24 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least ten, 2-theta (0) values selected from        those set forth in Table B below:

TABLE B °2θ d space (Å) Intensity (%) 12.26 ± 0.20 7.211 ± 0.117 2213.78 ± 0.20 6.421 ± 0.093 36 15.42 ± 0.20 5.741 ± 0.074 26 16.55 ± 0.205.352 ± 0.064 40 17.15 ± 0.20 5.167 ± 0.060 29 18.19 ± 0.20 4.873 ±0.053 100 18.50 ± 0.20 4.792 ± 0.051 100 19.45 ± 0.20 4.560 ± 0.046 3820.46 ± 0.20 4.338 ± 0.042 43 20.68 ± 0.20 4.291 ± 0.041 80 22.90 ± 0.203.880 ± 0.033 22 25.69 ± 0.20 3.466 ± 0.027 70

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.26 Any of formulae 1.1-1.25 wherein the Crystalline Form A        exhibits an XRPD pattern comprising the 2-theta (°) values set        forth in Table B of formula 1.25, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.27 Any of formulae 1.1-1.26 wherein the Crystalline Form A        exhibits an XRPD pattern having representative 2-theta (°)        values as set forth in Table B of formula 1.25, wherein the XRPD        is measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.28 Any of formulae 1.1-1.27 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least twelve, e.g., at least fifteen, e.g., at least twenty,        2-theta (0) values selected from the group consisting of 6.9,        12.3, 13.8, 14.5, 15.4, 16.6, 17.2, 18.2, 18.5, 19.5, 20.1,        20.5, 20.7, 21.0, 21.5, 22.9, 24.7, 25.2, 25.4, 25.7, 26.4,        27.5, and 27.8, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.29 Any of formulae 1.1-1.28 wherein the Crystalline Form A        exhibits an XRPD pattern comprising the following 2-theta (°)        values: 6.9, 12.3, 13.8, 14.5, 15.4, 16.6, 17.2, 18.2, 18.5,        19.5, 20.1, 20.5, 20.7, 21.0, 21.5, 22.9, 24.7, 25.2, 25.4,        25.7, 26.4, 27.5, and 27.8, wherein the XRPD is measured using        an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.30 Any of formulae 1.1-1.29 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least twelve, e.g., at least fifteen, e.g., at least twenty,        2-theta (0) values selected from the group consisting of 6.87,        12.26, 13.78, 14.49, 15.42, 16.55, 17.15, 18.19, 18.50, 19.45,        20.06, 20.46, 20.68, 20.96, 21.54, 22.90, 24.69, 25.17, 25.44,        25.69, 26.36, 27.52, and 27.76, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.31 Any of formulae 1.1-1.30 wherein the Crystalline Form A        exhibits an XRPD pattern comprising the following 2-theta (°)        values: 6.87, 12.26, 13.78, 14.49, 15.42, 16.55, 17.15, 18.19,        18.50, 19.45, 20.06, 20.46, 20.68, 20.96, 21.54, 22.90, 24.69,        25.17, 25.44, 25.69, 26.36, 27.52, and 27.76, wherein the XRPD        is measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.32 Any of formulae 1.1-1.31 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least twelve, e.g., at least fifteen, e.g., at least twenty,        2-theta (0) values selected from those set forth in Table C        below:

TABLE C °2θ d space (Å) Intensity (%)  6.87 ± 0.20 12.859 ± 0.374  612.26 ± 0.20 7.211 ± 0.117 22 13.78 ± 0.20 6.421 ± 0.093 36 14.49 ± 0.206.106 ± 0.084 6 15.42 ± 0.20 5.741 ± 0.074 26 16.55 ± 0.20 5.352 ± 0.06440 17.15 ± 0.20 5.167 ± 0.060 29 18.19 ± 0.20 4.873 ± 0.053 100 18.50 ±0.20 4.792 ± 0.051 100 19.45 ± 0.20 4.560 ± 0.046 38 20.06 ± 0.20 4.422± 0.044 9 20.46 ± 0.20 4.338 ± 0.042 43 20.68 ± 0.20 4.291 ± 0.041 8020.96 ± 0.20 4.236 ± 0.040 11 21.54 ± 0.20 4.123 ± 0.038 10 22.90 ± 0.203.880 ± 0.033 22 24.69 ± 0.20 3.602 ± 0.029 3 25.17 ± 0.20 3.535 ± 0.02814 25.44 ± 0.20 3.499 ± 0.027 13 25.69 ± 0.20 3.466 ± 0.027 70 26.36 ±0.20 3.378 ± 0.025 13 27.52 ± 0.20 3.239 ± 0.023 23 27.76 ± 0.20 3.211 ±0.023 7

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.33 Any of formulae 1.1-1.32 wherein the Crystalline Form A        exhibits an XRPD pattern comprising the 2-theta (°) values set        forth in Table C of formula 1.32, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.34 Any of formulae 1.1-1.33 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, d-spacing (A) values selected from the group        consisting of 5.7, 5.4, 5.2, 4.8, 4.6, 4.3, 3.9, and 3.5.    -   1.35 Any of formulae 1.1-1.34 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of 5.7,        5.4, 5.2, 4.8, 4.6, 4.3, 3.9, and 3.5.    -   1.36 Any of formulae 1.1-1.35 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, d-spacing (A) values selected from the group        consisting of 5.74, 5.35, 5.17, 4.79, 4.56, 4.34, 4.29, 3.88,        and 3.47.    -   1.37 Any of formulae 1.1-1.36 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of        5.74, 5.35, 5.17, 4.79, 4.56, 4.34, 4.29, 3.88, and 3.47.    -   1.38 Any of formulae 1.1-1.37 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, d-spacing (A) values selected from the group        consisting of 5.741, 5.352, 5.167, 4.792, 4.560, 4.338, 4.291,        3.880, and 3.466.    -   1.39 Any of formulae 1.1-1.38 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of        5.741, 5.352, 5.167, 4.792, 4.560, 4.338, 4.291, 3.880, and        3.466.    -   1.40 Any of formulae 1.1-1.39 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, d-spacing (A) values selected from those set forth        in Table A of formula 1.16.    -   1.41 Any of formulae 1.1-1.40 wherein the Crystalline Form A        exhibits an XRPD pattern comprising the d-spacing (A) values set        forth in Table A of formula 1.16.    -   1.42 Any of formulae 1.1-1.41 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least ten, d-spacing (A) values selected        from the group consisting of 7.2, 6.4, 5.7, 5.4, 5.2, 4.9, 4.8,        4.6, 4.3, 3.9, and 3.5.    -   1.43 Any of formulae 1.1-1.42 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of 7.2,        6.4, 5.7, 5.4, 5.2, 4.9, 4.8, 4.6, 4.3, 3.9, and 3.5.    -   1.44 Any of formulae 1.1-1.43 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least ten, d-spacing (A) values selected        from the group consisting of 7.21, 6.42, 5.74, 5.35, 5.17, 4.87,        4.79, 4.56, 4.34, 4.29, 3.88, and 3.47.    -   1.45 Any of formulae 1.1-1.44 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of        7.21, 6.42, 5.74, 5.35, 5.17, 4.87, 4.79, 4.56, 4.34, 4.29,        3.88, and 3.47.    -   1.46 Any of formulae 1.1-1.45 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least ten, d-spacing (A) values selected        from the group consisting of 7.211, 6.421, 5.741, 5.352, 5.167,        4.873, 4.792, 4.560, 4.338, 4.291, 3.880, and 3.466.    -   1.47 Any of formulae 1.1-1.46 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of        7.211, 6.421, 5.741, 5.352, 5.167, 4.873, 4.792, 4.560, 4.338,        4.291, 3.880, and 3.466.    -   1.48 Any of formulae 1.1-1.47 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least ten, d-spacing (A) values selected        from those set forth in Table B of formula 1.25.    -   1.49 Any of formulae 1.1-1.48 wherein the Crystalline Form A        exhibits an XRPD pattern comprising the d-spacing (A) values set        forth in Table B of formula 1.25.    -   1.50 Any of formulae 1.1-1.49 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least twelve, e.g., at least fifteen, d-spacing (A) values        selected from the group consisting of 12.9, 7.2, 6.4, 6.1, 5.7,        5.4, 5.2, 4.9, 4.8, 4.6, 4.4, 4.3, 4.2, 4.1, 3.9, 3.6, 3.5, 3.4,        and 3.2.    -   1.51 Any of formulae 1.1-1.50 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of        12.9, 7.2, 6.4, 6.1, 5.7, 5.4, 5.2, 4.9, 4.8, 4.6, 4.4, 4.3,        4.2, 4.1, 3.9, 3.6, 3.5, 3.4, and 3.2.    -   1.52 Any of formulae 1.1-1.51 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least twelve, e.g., at least fifteen, e.g., at least twenty,        d-spacing (A) values selected from the group consisting of        12.86, 7.21, 6.42, 6.11, 5.74, 5.35, 5.17, 4.87, 4.79, 4.56,        4.42, 4.34, 4.29, 4.24, 4.12, 3.88, 3.60, 3.54, 3.50, 3.47,        3.38, 3.24, and 3.21.    -   1.53 Any of formulae 1.1-1.52 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of        12.86, 7.21, 6.42, 6.11, 5.74, 5.35, 5.17, 4.87, 4.79, 4.56,        4.42, 4.34, 4.29, 4.24, 4.12, 3.88, 3.60, 3.54, 3.50, 3.47,        3.38, 3.24, and 3.21.    -   1.54 Any of formulae 1.1-1.53 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least twelve, e.g., at least fifteen, e.g., at least twenty,        d-spacing (A) values selected from the group consisting of        12.859, 7.211, 6.421, 6.106, 5.741, 5.352, 5.167, 4.873, 4.792,        4.560, 4.422, 4.338, 4.291, 4.236, 4.123, 3.880, 3.602, 3.535,        3.499, 3.466, 3.378, 3.239, and 3.211.    -   1.55 Any of formulae 1.1-1.54 wherein the Crystalline Form A        exhibits an XRPD pattern comprising d-spacing (A) values of        12.859, 7.211, 6.421, 6.106, 5.741, 5.352, 5.167, 4.873, 4.792,        4.560, 4.422, 4.338, 4.291, 4.236, 4.123, 3.880, 3.602, 3.535,        3.499, 3.466, 3.378, 3.239, and 3.211.    -   1.56 Any of formulae 1.1-1.55 wherein the Crystalline Form A        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least twelve, e.g., at least fifteen, e.g., at least twenty,        d-spacing (A) values selected from those set forth in Table C of        formula 1.32.    -   1.57 Any of formulae 1.1-1.56 wherein the Crystalline Form A        exhibits an XRPD pattern comprising the d-spacing (A) values set        forth in Table C of formula 1.32.    -   1.58 Any of formulae 1.1-1.57 wherein the Crystalline Form A        exhibits an XRPD pattern comprising characteristic peaks of the        XRPD pattern shown in FIG. 1, wherein the XRPD is measured using        Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.59 Any of formulae 1.1-1.58 wherein the Crystalline Form A        exhibits an XRPD pattern comprising representative peaks of the        XRPD pattern shown in FIG. 1, wherein the XRPD is measured using        Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.60 Any of formulae 1.1-1.59 wherein the Crystalline Form A        exhibits an X-ray powder diffraction (XRPD) pattern, e.g., an        X-ray powder diffraction pattern measured using an incident beam        of Cu radiation, e.g., Cu Kα radiation, e.g., a high-resolution        X-ray powder diffraction pattern measured using an incident beam        of Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å, comprising three peaks, in        some embodiments, five peaks, selected from those shown in FIG.        1.    -   1.61 Any of formulae 1.1-1.60 wherein the Crystalline Form A        exhibits an XRPD pattern, e.g., an XRPD pattern measured using        an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., a        high-resolution XRPD pattern measured using an incident beam of        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å, comprising at least nine        peaks, e.g., at least ten peaks, e.g., at least twelve peaks,        e.g., at least fifteen peaks, e.g., at least twenty peaks,        selected from those shown in FIG. 1.    -   1.62 Any of formulae 1.1-1.61 wherein the Crystalline Form A        exhibits an X-ray powder diffraction (XRPD) pattern, e.g., an        X-ray powder diffraction pattern measured using an incident beam        of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD        is measured using radiation of wavelength 1.54059 Å,        substantially as shown in FIG. 1.    -   1.63 Any of formulae 1.1-1.62 wherein the Crystalline Form A        exhibits an X-ray powder diffraction (XRPD) pattern, e.g., an        X-ray powder diffraction pattern measured using an incident beam        of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD        is measured using radiation of wavelength 1.54059 Å, as shown in        FIG. 1.    -   1.64 Any of formulae 1.1-1.63 wherein the Crystalline Form A        exhibits an XRPD pattern comprising characteristic peaks of the        XRPD pattern shown in any of FIGS. 1, 35, 37, and 47, e.g., FIG.        1, e.g., FIG. 35, e.g., FIG. 37, e.g., FIG. 47, wherein the XRPD        is measured using Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.65 Any of formulae 1.1-1.64 wherein the Crystalline Form A        exhibits an XRPD pattern comprising representative peaks of the        XRPD pattern shown in any of FIGS. 1, 35, 37, and 47, e.g., FIG.        1, e.g., FIG. 35, e.g., FIG. 37, e.g., FIG. 47, wherein the XRPD        is measured using Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.66 Any of formulae 1.1-1.65 wherein the Crystalline Form A        exhibits an XRPD pattern, e.g., an XRPD pattern measured using        an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., a        high-resolution XRPD pattern measured using an incident beam of        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å, comprising three peaks, in        some embodiments, five peaks, selected from those shown in any        of FIGS. 1, 35, 37, and 47, e.g., FIG. 1, e.g., FIG. 35, e.g.,        FIG. 37, e.g., FIG. 47.    -   1.67 Any of formulae 1.1-1.66 wherein the Crystalline Form A        exhibits an XRPD pattern, e.g., an XRPD pattern measured using        an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g., a        high-resolution XRPD pattern measured using an incident beam of        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å, comprising at least nine        peaks, e.g., at least ten peaks, e.g., at least twelve peaks,        e.g., at least fifteen peaks, e.g., at least twenty peaks,        selected from those shown in any of FIGS. 1, 35, 37, and 47,        e.g., FIG. 1, e.g., FIG. 35, e.g., FIG. 37, e.g., FIG. 47.    -   1.68 Any of formulae 1.1-1.67 wherein the Crystalline Form A        exhibits an XRPD pattern, e.g., an XRPD pattern measured using        an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å, substantially as shown in any of FIGS. 1, 35, 37, and        47, e.g., FIG. 1, e.g., FIG. 35, e.g., FIG. 37, e.g., FIG. 47.    -   1.69 Any of formulae 1.1-1.68 wherein the Crystalline Form A        exhibits an XRPD pattern, e.g., an XRPD pattern measured using        an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å, as shown in any of FIGS. 1, 35, 37, and 47, e.g.,        FIG. 1, e.g., FIG. 35, e.g., FIG. 37, e.g., FIG. 47.    -   1.70 Any of formulae 1.1-1.69 wherein the Crystalline Form A        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak between 245° C. and 249° C.,        e.g., between 245° C. and 248° C., e.g., wherein the Crystalline        Form A exhibits a differential scanning calorimetry (DSC)        thermogram comprising multiple, e.g., three, endotherms between        245° C. and 249° C., e.g., between 245° C. and 248° C., e.g.,        wherein the Crystalline Form A exhibits a differential scanning        calorimetry (DSC) thermogram comprising an endothermic peak at        247° C. with an onset at 245° C., an endothermic shoulder at        248° C., and an endothermic peak at 248° C.    -   1.71 Any of formulae 1.1-1.70 wherein the Crystalline Form A        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 247° C., e.g., an endothermic        peak at 247° C. with an onset at 245° C.    -   1.72 Any of formulae 1.1-1.71 wherein the Crystalline Form A        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 248° C.    -   1.73 Any of formulae 1.1-1.72 wherein the Crystalline Form A        exhibits a differential scanning calorimetry (DSC) thermogram as        shown in FIG. 2.    -   1.74 Any of formulae 1.1-1.73 wherein the Crystalline Form A        exhibits a thermogravimetric analysis (TGA) thermogram        comprising 0.4% weight loss up to 200° C.    -   1.75 Any of formulae 1.1-1.74 having a thermogravimetric        analysis (TGA) thermogram comprising an onset decomposition        temperature at 276° C.    -   1.76 Any of formulae 1.1-1.75 wherein the Crystalline Form A        exhibits a thermogravimetric analysis (TGA) thermogram as shown        in FIG. 2.    -   1.77 Any of formulae 1.1-1.76 wherein the Crystalline Form A        exhibits a dynamic vapor sorption/desporption isotherm as shown        in FIG. 3, e.g., a dynamic vapor sorption/desporption isotherm        wherein Crystalline Form A shows:        -   a weight loss of 0.03% upon equilibration at 5% RH;        -   a weight gain of 0.10% from 5% to 95% RH; and        -   a 0.10% weight loss from 95% to 5% RH.    -   1.78 Crystalline Form B of the Compound in hydrochloric acid        addition salt form        ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride) (“Crystalline Form B”).    -   1.79 Formula 1.78 wherein the Crystalline Form B belongs to the        P2₁2₁2₁ space group and has the following unit cell parameters:        -   a=5.9055(2) Å, b=7.4645(3) Å, c=29.1139(13) Å, α=β=γ=90°.    -   1.80 Formula 1.78 wherein the Crystalline Form B belongs to the        P2₁2₁2₁ space group and has any combination of the following        unit cell parameters:        -   a=5-7 Å, e.g., 6 Å, e.g., 5.7-6.1 Å, e.g., 5.8-6.0 Å, e.g.,            5.9 Å, e.g., 5.91, e.g., 5.906 Å;        -   b=6-8 Å, e.g., 7 Å, e.g., 7.3-7.7 Å, e.g., 7.4-7.6 Å, e.g.,            7.5 Å, e.g., 7.46 Å, e.g., 7.465 Å;        -   c=28-30 Å, e.g., 29 Å, e.g., 28.9-29.3 Å, e.g., 29.0-29.2 Å,            e.g., 29.1 Å, e.g., 29.11 Å, e.g., 29.114 Å; and        -   α=β=γ=90°.    -   1.81 Any of formulae 1.78-1.80 wherein the Crystalline Form B        has a calculated volume of V=1283.39(9) Å³.    -   1.82 Any of formulae 1.78-1.81 wherein the crystal structure of        the Crystalline Form B is obtained with a crystal having        approximate dimensions of 0.31 mm×0.21 mm×0.09 mm, e.g., a        colorless plate having approximate dimensions of 0.31 mm×0.21        mm×0.09 mm.    -   1.83 Any of formulae 1.78-1.82 wherein the crystal structure of        the Crystalline Form B is obtained with Cu Kα radiation, e.g.,        Cu Kα having λ=1.54178 Å.    -   1.84 Any of formulae 1.78-1.83 wherein the crystal structure of        the Crystalline Form B is obtained at 100(2) K.    -   1.85 Any of formulae 1.78-1.84 wherein the Crystalline Form B        has a single crystal structure represented by the atomic        displacement ellipsoid drawing of FIG. 24.    -   1.86 Any of formulae 1.78-1.85 wherein the Crystalline Form B        has a calculated XRPD pattern as shown in FIG. 32.    -   1.87 Any of formulae 1.78-1.86 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three 2-theta (°)        values selected from the group consisting of 6.0, 17.4, 18.9,        19.2, and 24.4, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.88 Any of formulae 1.78-1.87 wherein the Crystalline Form B        exhibits an XRPD pattern comprising 2-theta (°) values of 6.0,        17.4, 18.9, 19.2, and 24.4, wherein the XRPD is measured using        an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.89 Any of formulae 1.78-1.88 wherein the Crystalline Form B        exhibits an XRPD pattern having characteristic 2-theta (°)        values of 6.0, 17.4, 18.9, 19.2, and 24.4, wherein the XRPD is        measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.90 Any of formulae 1.78-1.89 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three 2-theta (°)        values selected from the group consisting of 6.04, 17.41, 18.94,        19.19, and 24.39, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.91 Any of formulae 1.78-1.90 wherein the Crystalline Form B        exhibits an XRPD pattern comprising 2-theta (°) values of 6.04,        17.41, 18.94, 19.19, and 24.39, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.92 Any of formulae 1.78-1.91 wherein the Crystalline Form B        exhibits an XRPD pattern having characteristic 2-theta (°)        values of 6.04, 17.41, 18.94, 19.19, and 24.39, wherein the XRPD        is measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.93 Any of formulae 1.78-1.92 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three 2-theta (°)        values selected from those set forth in Table D below:

TABLE D °2θ d space (Å) Intensity (%)  6.04 ± 0.20 14.620 ± 0.484  1317.41 ± 0.20 5.089 ± 0.058 14 18.94 ± 0.20 4.681 ± 0.049 79 19.19 ± 0.204.622 ± 0.048 100 24.39 ± 0.20 3.646 ± 0.029 23

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.94 Any of formulae 1.78-1.93 wherein the Crystalline Form B        exhibits an XRPD pattern comprising the 2-theta (°) values set        forth in Table D of formula 1.93, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.95 Any of formulae 1.78-1.94 wherein the Crystalline Form B        exhibits an XRPD pattern having characteristic 2-theta (°)        values as set forth in Table D of formula 1.93, wherein the XRPD        is measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.96 Any of formulae 1.78-1.95 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, 2-theta (°) values selected from the group        consisting of 6.0, 13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4, and        28.2, wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.97 Any of formulae 1.78-1.96 wherein the Crystalline Form B        exhibits an XRPD pattern comprising 2-theta (°) values of 6.0,        13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4, and 28.2, wherein the        XRPD is measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.98 Any of formulae 1.78-1.97 wherein the Crystalline Form B        exhibits an XRPD pattern having representative 2-theta (°)        values of 6.0, 13.2, 17.4, 18.9, 19.2, 23.6, 23.8, 24.4, and        28.2, wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.99 Any of formulae 1.78-1.98 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, 2-theta (°) values selected from the group        consisting of 6.04, 13.21, 17.41, 18.94, 19.19, 23.59, 23.79,        24.39, and 28.15, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.100 Any of formulae 1.78-1.99 wherein the Crystalline Form B        exhibits an XRPD pattern comprising 2-theta (°) values of 6.04,        13.21, 17.41, 18.94, 19.19, 23.59, 23.79, 24.39, and 28.15,        wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.101 Any of formulae 1.78-1.100 wherein the Crystalline Form B        exhibits an XRPD pattern having representative 2-theta (°)        values of 6.04, 13.21, 17.41, 18.94, 19.19, 23.59, 23.79, 24.39,        and 28.15, wherein the XRPD is measured using an incident beam        of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD        is measured using radiation of wavelength 1.54059 Å.    -   1.102 Any of formulae 1.78-1.101 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, 2-theta (°) values selected from those set forth in        Table E below:

TABLE E °2θ d space (Å) Intensity (%)  6.04 ± 0.20 14.620 ± 0.484  1313.21 ± 0.20 6.699 ± 0.101 21 17.41 ± 0.20 5.089 ± 0.058 14 18.94 ± 0.204.681 ± 0.049 79 19.19 ± 0.20 4.622 ± 0.048 100 23.59 ± 0.20 3.769 ±0.032 16 23.79 ± 0.20 3.737 ± 0.031 43 24.39 ± 0.20 3.646 ± 0.029 2328.15 ± 0.20 3.168 ± 0.022 24

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.103 Any of formulae 1.78-1.102 wherein the Crystalline Form B        exhibits an XRPD pattern comprising the 2-theta (°) values set        forth in Table E of formula 1.102, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.104 Any of formulae 1.78-1.103 wherein the Crystalline Form B        exhibits an XRPD pattern having representative 2-theta (°)        values as set forth in Table E of formula 1.102, wherein the        XRPD is measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.105 Any of formulae 1.78-1.104 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least fifteen, e.g., at least twenty, e.g., at least        twenty-five, 2-theta (0) values selected from the group        consisting of 6.0, 12.1, 13.2, 14.9, 15.1, 16.0, 16.9, 17.4,        18.2, 18.9, 19.2, 19.9, 21.1, 21.3, 21.7, 22.6, 23.6, 23.8,        24.4, 25.3, 26.1, 26.6, 27.2, 28.2, 28.7, and 29.5, wherein the        XRPD is measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.106 Any of formulae 1.78-1.105 wherein the Crystalline Form B        exhibits an XRPD pattern comprising the following 2-theta (°)        values: 6.0, 12.1, 13.2, 14.9, 15.1, 16.0, 16.9, 17.4, 18.2,        18.9, 19.2, 19.9, 21.1, 21.3, 21.7, 22.6, 23.6, 23.8, 24.4,        25.3, 26.1, 26.6, 27.2, 28.2, 28.7, and 29.5, wherein the XRPD        is measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.107 Any of formulae 1.78-1.106 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least fifteen, e.g., at least twenty, e.g., at least        twenty-five, 2-theta (0) values selected from the group        consisting of 6.04, 12.12, 13.21, 14.86, 15.13, 16.02, 16.90,        17.41, 18.23, 18.94, 19.19, 19.91, 21.05, 21.27, 21.74, 22.55,        23.59, 23.79, 24.39, 25.34, 26.06, 26.61, 27.15, 28.15, 28.66,        and 29.47, wherein the XRPD is measured using an incident beam        of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD        is measured using radiation of wavelength 1.54059 Å.    -   1.108 Any of formulae 1.78-1.107 wherein the Crystalline Form B        exhibits an XRPD pattern comprising the following 2-theta (°)        values: 6.04, 12.12, 13.21, 14.86, 15.13, 16.02, 16.90, 17.41,        18.23, 18.94, 19.19, 19.91, 21.05, 21.27, 21.74, 22.55, 23.59,        23.79, 24.39, 25.34, 26.06, 26.61, 27.15, 28.15, 28.66, and        29.47, wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.109 Any of formulae 1.78-1.108 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least fifteen, e.g., at least twenty, e.g., at least        twenty-five, e.g., at least five, 2-theta (°) values selected        from those set forth in Table F below:

TABLE F °2θ d space (Å) Intensity (%)  6.04 ± 0.20 14.620 ± 0.484  1312.12 ± 0.20 7.296 ± 0.120 6 13.21 ± 0.20 6.699 ± 0.101 21 14.86 ± 0.205.958 ± 0.080 8 15.13 ± 0.20 5.853 ± 0.077 5 16.02 ± 0.20 5.529 ± 0.0691 16.90 ± 0.20 5.242 ± 0.062 4 17.41 ± 0.20 5.089 ± 0.058 14 18.23 ±0.20 4.861 ± 0.053 10 18.94 ± 0.20 4.681 ± 0.049 79 19.19 ± 0.20 4.622 ±0.048 100 19.91 ± 0.20 4.457 ± 0.044 4 21.05 ± 0.20 4.217 ± 0.040 1121.27 ± 0.20 4.173 ± 0.039 2 21.74 ± 0.20 4.085 ± 0.037 4 22.55 ± 0.203.939 ± 0.034 6 23.59 ± 0.20 3.769 ± 0.032 16 23.79 ± 0.20 3.737 ± 0.03143 24.39 ± 0.20 3.646 ± 0.029 23 25.34 ± 0.20 3.512 ± 0.027 1 26.06 ±0.20 3.416 ± 0.026 2 26.61 ± 0.20 3.347 ± 0.025 1 27.15 ± 0.20 3.282 ±0.024 2 28.15 ± 0.20 3.168 ± 0.022 24 28.66 ± 0.20 3.112 ± 0.021 1329.47 ± 0.20 3.028 ± 0.020 13

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.110 Any of formulae 1.78-1.109 wherein the Crystalline Form B        exhibits an XRPD pattern comprising the 2-theta (°) values set        forth in Table F of formula 1.109, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.111 Any of formulae 1.78-1.110 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three d-spacing (A)        values selected from the group consisting of 14.6, 5.1, 4.7,        4.6, and 3.6.    -   1.112 Any of formulae 1.78-1.111 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.6, 5.1, 4.7, 4.6, and 3.6.    -   1.113 Any of formulae 1.78-1.112 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three d-spacing (A)        values selected from the group consisting of 14.62, 5.09, 4.68,        4.62, and 3.65.    -   1.114 Any of formulae 1.78-1.113 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.62, 5.09, 4.68, 4.62, and 3.65.    -   1.115 Any of formulae 1.78-1.114 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three d-spacing (A)        values selected from the group consisting of 14.620, 5.089,        4.681, 4.622, and 3.646.    -   1.116 Any of formulae 1.78-1.115 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.620, 5.089, 4.681, 4.622, and 3.646.    -   1.117 Any of formulae 1.78-1.116 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three d-spacing (A)        values selected from those set forth in Table D of formula 1.93.    -   1.118 Any of formulae 1.78-1.117 wherein the Crystalline Form B        exhibits an XRPD pattern comprising the d-spacing (A) values set        forth in Table D of formula 1.93.    -   1.119 Any of formulae 1.78-1.118 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, d-spacing (A) values selected from the group        consisting of 14.6, 6.7, 5.1, 4.7, 4.6, 3.8, 3.7, 3.6, and 3.2.    -   1.120 Any of formulae 1.78-1.119 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.6, 6.7, 5.1, 4.7, 4.6, 3.8, 3.7, 3.6, and 3.2.    -   1.121 Any of formulae 1.78-1.120 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, d-spacing (A) values selected from the group        consisting of 14.62, 6.70, 5.09, 4.68, 4.62, 3.77, 3.74, 3.65,        and 3.17.    -   1.122 Any of formulae 1.78-1.121 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.62, 6.70, 5.09, 4.68, 4.62, 3.77, 3.74, 3.65, and 3.17.    -   1.123 Any of formulae 1.78-1.122 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, d-spacing (A) values selected from the group        consisting of 14.620, 6.699, 5.089, 4.681, 4.622, 3.769, 3.737,        3.646, and 3.168.    -   1.124 Any of formulae 1.78-1.123 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.620, 6.699, 5.089, 4.681, 4.622, 3.769, 3.737, 3.646, and        3.168.    -   1.125 Any of formulae 1.78-1.124 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, d-spacing (A) values selected from those set forth        in Table E of formula 1.102.    -   1.126 Any of formulae 1.78-1.125 wherein the Crystalline Form B        exhibits an XRPD pattern comprising the d-spacing (A) values set        forth in Table E of formula 1.102.    -   1.127 Any of formulae 1.78-1.126 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least fifteen, e.g., at least twenty, d-spacing (A) values        selected from the group consisting of 14.6, 7.3, 6.7, 6.0, 5.9,        5.5, 5.2, 5.1, 4.9, 4.7, 4.6, 4.5, 4.2, 4.1, 3.9, 3.8, 3.7, 3.6,        3.5, 3.4, 3.3, 3.2, 3.1, and 3.0.    -   1.128 Any of formulae 1.78-1.127 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.6, 7.3, 6.7, 6.0, 5.9, 5.5, 5.2, 5.1, 4.9, 4.7, 4.6, 4.5,        4.2, 4.1, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, and 3.0.    -   1.129 Any of formulae 1.78-1.128 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least fifteen, e.g., at least twenty, e.g., at least        twenty-five, d-spacing (A) values selected from the group        consisting of 14.62, 7.30, 6.70, 5.96, 5.85, 5.53, 5.24, 5.09,        4.86, 4.68, 4.62, 4.46, 4.22, 4.17, 4.09, 3.94, 3.77, 3.74,        3.65, 3.51, 3.42, 3.35, 3.28, 3.17, 3.11, and 3.03.    -   1.130 Any of formulae 1.78-1.129 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.62, 7.30, 6.70, 5.96, 5.85, 5.53, 5.24, 5.09, 4.86, 4.68,        4.62, 4.46, 4.22, 4.17, 4.09, 3.94, 3.77, 3.74, 3.65, 3.51,        3.42, 3.35, 3.28, 3.17, 3.11, and 3.03.    -   1.131 Any of formulae 1.78-1.130 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least fifteen, e.g., at least twenty, e.g., at least        twenty-five, d-spacing (A) values selected from the group        consisting of 14.620, 7.296, 6.699, 5.958, 5.853, 5.529, 5.242,        5.089, 4.861, 4.681, 4.622, 4.457, 4.217, 4.173, 4.085, 3.939,        3.769, 3.737, 3.646, 3.512, 3.416, 3.347, 3.282, 3.168, 3.112,        and 3.028.    -   1.132 Any of formulae 1.78-1.131 wherein the Crystalline Form B        exhibits an XRPD pattern comprising d-spacing (A) values of        14.620, 7.296, 6.699, 5.958, 5.853, 5.529, 5.242, 5.089, 4.861,        4.681, 4.622, 4.457, 4.217, 4.173, 4.085, 3.939, 3.769, 3.737,        3.646, 3.512, 3.416, 3.347, 3.282, 3.168, 3.112, and 3.028.    -   1.133 Any of formulae 1.78-1.132 wherein the Crystalline Form B        exhibits an XRPD pattern comprising at least three, e.g., at        least five, e.g., at least nine, e.g., at least ten, e.g., at        least fifteen, e.g., at least twenty, e.g., at least        twenty-five, d-spacing (A) values selected from those set forth        in Table F of formula 1.109.    -   1.134 Any of formulae 1.78-1.133 wherein the Crystalline Form B        exhibits an XRPD pattern comprising the d-spacing (A) values set        forth in Table F of formula 1.109.    -   1.135 Any of formulae 1.78-1.134 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern comprising        characteristic peaks of the XRPD pattern shown in FIG. 5,        wherein the XRPD is measured using Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.541871 Å.    -   1.136 Any of formulae 1.78-1.135 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern comprising        representative peaks of the XRPD pattern shown in FIG. 5,        wherein the XRPD is measured using Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.541871 Å.    -   1.137 Any of formulae 1.78-1.136 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        three peaks, in some embodiments, five peaks, selected from        those shown in FIG. 5.    -   1.138 Any of formulae 1.78-1.137 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising at        least five peaks, e.g., at least nine peaks, e.g., at least ten        peaks, e.g., at least fifteen peaks, e.g., at least twenty        peaks, e.g., at least twenty-five peaks, selected from those        shown in FIG. 5.    -   1.139 Any of formulae 1.78-1.138 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, substantially        as shown in FIG. 5.    -   1.140 Any of formulae 1.78-1.139 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, as shown in        FIG. 5.    -   1.141 Any of formulae 1.78-1.140 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern comprising        characteristic peaks of the XRPD pattern shown in FIG. 7,        wherein the XRPD is measured using Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å, e.g., wherein XRPD pattern also comprises        peaks of Crystalline Form A (e.g., a mixture of Crystalline        Forms A and B).    -   1.142 Any of formulae 1.78-1.141 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern comprising        representative peaks of the XRPD pattern shown in FIG. 7,        wherein the XRPD is measured using Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å, e.g., wherein XRPD pattern also comprises        peaks of Crystalline Form A (e.g., a mixture of Crystalline        Forms A and B).    -   1.143 Any of formulae 1.78-1.142 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray        powder diffraction pattern measured using an incident beam of Cu        Kα radiation, e.g., wherein the XRPD is measured using radiation        of wavelength 1.54059 Å, comprising three peaks, in some        embodiments, five peaks, selected from those shown in FIG. 7,        e.g., wherein XRPD pattern also comprises peaks of Crystalline        Form A (e.g., a mixture of Crystalline Forms A and B).    -   1.144 Any of formulae 1.78-1.143 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray        powder diffraction pattern measured using an incident beam of Cu        Kα radiation, e.g., wherein the XRPD is measured using radiation        of wavelength 1.54059 Å, comprising at least five peaks, e.g.,        at least nine peaks, e.g., at least ten peaks, e.g., at least        fifteen peaks, e.g., at least twenty peaks, e.g., at least        twenty-five peaks, selected from those shown in FIG. 7, e.g.,        wherein XRPD pattern comprises peaks of Crystalline Form A        (e.g., a mixture of Crystalline Forms A and B).    -   1.145 Any of formulae 1.78-1.144 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray        powder diffraction pattern measured using an incident beam of Cu        Kα radiation, e.g., wherein the XRPD is measured using radiation        of wavelength 1.54059 Å, substantially as shown in FIG. 7, e.g.,        wherein XRPD pattern comprises peaks of Crystalline Form A        (e.g., a mixture of Crystalline Forms A and B).    -   1.146 Any of formulae 1.78-1.145 wherein the Crystalline Form B        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray        powder diffraction pattern measured using an incident beam of Cu        Kα radiation, e.g., wherein the XRPD is measured using radiation        of wavelength 1.54059 Å, as shown in FIG. 7, e.g., wherein XRPD        pattern comprises peaks of Crystalline Form A (e.g., a mixture        of Crystalline Forms A and B).    -   1.147 Any of formulae 1.78-1.146 wherein the Crystalline Form B        exhibits an XRPD pattern comprising characteristic peaks of the        XRPD pattern shown in any of FIGS. 7, 40, and 48, e.g., FIG. 7,        e.g., FIG. 40, e.g., FIG. 48, wherein the XRPD is measured using        Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.148 Any of formulae 1.78-1.147 wherein the Crystalline Form B        exhibits an XRPD pattern comprising representative peaks of the        XRPD pattern shown in any of FIGS. 7, 40, and 48, e.g., FIG. 7,        e.g., FIG. 40, e.g., FIG. 48, wherein the XRPD is measured using        Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.149 Any of formulae 1.78-1.148 wherein the Crystalline Form B        exhibits an XRPD pattern, e.g., an X-ray powder diffraction        pattern measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., a high-resolution X-ray powder        diffraction pattern measured using an incident beam of Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å, comprising three peaks, in some        embodiments, five peaks, selected from those shown in any of        FIGS. 7, 40, and 48, e.g., FIG. 7, e.g., FIG. 40, e.g., FIG. 48.    -   1.150 Any of formulae 1.78-1.149 wherein the Crystalline Form B        exhibits an XRPD pattern, e.g., an X-ray powder diffraction        pattern measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., a high-resolution X-ray powder        diffraction pattern measured using an incident beam of Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å, comprising at least five, e.g., at least        nine, e.g., at least ten, e.g., at least fifteen, e.g., at least        twenty, e.g., at least twenty-five, selected from those shown in        any of FIGS. 7, 40, and 48, e.g., FIG. 7, e.g., FIG. 40, e.g.,        FIG. 48.    -   1.151 Any of formulae 1.78-1.150 wherein the Crystalline Form B        exhibits an XRPD pattern, e.g., an X-ray powder diffraction        pattern measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å, substantially as shown in any        of FIGS. 7, 40, and 48, e.g., FIG. 7, e.g., FIG. 40, e.g., FIG.        48.    -   1.152 Any of formulae 1.1-1.151 wherein the Crystalline Form B        exhibits an X-ray powder diffraction (XRPD) pattern, e.g., an        X-ray powder diffraction pattern measured using an incident beam        of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD        is measured using radiation of wavelength 1.54059 Å, as shown in        any of FIGS. 7, 40, and 48, e.g., FIG. 7, e.g., FIG. 40, e.g.,        FIG. 48.    -   1.153 Any of formulae 1.78-1.152 wherein the Crystalline Form B        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak between 247° C. and 248° C.    -   1.154 Any of formulae 1.78-1.153 wherein the Crystalline Form B        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 247° C.    -   1.155 Any of formulae 1.78-1.154 wherein the Crystalline Form B        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 248° C., e.g., an endothermic        peak at 248° C. with an onset at 246° C.    -   1.156 Any of formulae 1.78-1.155 wherein the Crystalline Form B        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 251° C.    -   1.157 Any of formulae 1.78-1.156 wherein the Crystalline Form B        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 264° C.    -   1.158 Any of formulae 1.78-1.157 wherein the Crystalline Form B        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 141° C., e.g., an endothermic        peak at 141° C. with an onset between 137° C. and 138° C., e.g.,        an endothermic peak at 141° C. with an onset at 137° C., e.g.,        an endothermic peak at 141° C. with an onset at 138° C.    -   1.159 Any of formulae 1.78-1.158 wherein the Crystalline Form B        exhibits a differential scanning calorimetry (DSC) thermogram as        shown in FIG. 8.    -   1.160 Any of formulae 1.78-1.159 wherein the Crystalline Form B        exhibits a thermogravimetric analysis (TGA) thermogram        comprising 0.2% weight loss up to 200° C.    -   1.161 Any of formulae 1.78-1.160 wherein the Crystalline Form B        exhibits a thermogravimetric analysis (TGA) thermogram        comprising an onset decomposition temperature at 281° C.    -   1.162 Any of formulae 1.78-1.161 wherein the Crystalline Form B        exhibits a thermogravimetric analysis (TGA) thermogram as shown        in FIG. 8.    -   1.163 Crystalline Form C of the Compound in hydrochloric acid        addition salt form        ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride) (“Crystalline Form C”).    -   1.164 Formula 1.163 wherein the Crystalline Form C exhibits an        XRPD pattern comprising a 2-theta (°) value of 17.7, wherein the        XRPD is measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.165 Formula 1.163 or 1.164 wherein the Crystalline Form C        exhibits an XRPD pattern having a characteristic 2-theta (°)        value of 17.7, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.166 Any of formulae 1.163-1.165 wherein the Crystalline Form C        exhibits an XRPD pattern comprising a 2-theta (°) value of        17.74, wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.167 Any of formulae 1.163-1.166 wherein the Crystalline Form C        exhibits an XRPD pattern having a characteristic 2-theta (°)        value of 17.74, wherein the XRPD is measured using an incident        beam of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the        XRPD is measured using radiation of wavelength 1.54059 Å.    -   1.168 Any of formulae 1.163-1.167 wherein the Crystalline Form C        exhibits an XRPD pattern comprising a 2-theta (°) value in Table        G below:

TABLE G °2θ d space (Å) Intensity (%) 17.74 ± 0.20 4.994 ± 0.056 100

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.169 Any of formulae 1.163-1.168 wherein the Crystalline Form C        exhibits an XRPD pattern having characteristic 2-theta (°) value        as set forth in Table G of formula 1.168, wherein the XRPD is        measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.170 Any of formulae 1.163-1.169 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, 2-theta (0) values selected from the        group consisting of 7.0, 13.2, 14.4, 17.7, 18.0, 19.9, 21.3,        22.6, 23.7, and 26.5, wherein the XRPD is measured using an        incident beam of Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.171 Any of formulae 1.163-1.170 wherein the Crystalline Form C        exhibits an XRPD pattern comprising 2-theta (°) values of 7.0,        13.2, 14.4, 17.7, 18.0, 19.9, 21.3, 22.6, 23.7, and 26.5,        wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.172 Any of formulae 1.163-1.171 wherein the Crystalline Form C        exhibits an XRPD pattern having representative 2-theta (°)        values of 7.0, 13.2, 14.4, 17.7, 18.0, 19.9, 21.3, 22.6, 23.7,        and 26.5, wherein the XRPD is measured using an incident beam of        Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.173 Any of formulae 1.163-1.172 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, 2-theta (°)        values selected from the group consisting of 6.97, 13.24, 14.39,        17.74, 17.98, 18.03, 19.85, 21.32, 22.60, 23.68, and 26.52,        wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.174 Any of formulae 1.163-1.173 wherein the Crystalline Form C        exhibits an XRPD pattern comprising 2-theta (°) values of 6.97,        13.24, 14.39, 17.74, 17.98, 18.03, 19.85, 21.32, 22.60, 23.68,        and 26.52, wherein the XRPD is measured using an incident beam        of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD        is measured using radiation of wavelength 1.54059 Å.    -   1.175 Any of formulae 1.163-1.174 wherein the Crystalline Form C        exhibits an XRPD pattern having representative 2-theta (°)        values of 6.97, 13.24, 14.39, 17.74, 17.98, 18.03, 19.85, 21.32,        22.60, 23.68, and 26.52, wherein the XRPD is measured using an        incident beam of Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.176 Any of formulae 1.163-1.175 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, 2-theta (°)        values selected from those set forth in Table H below:

TABLE H °2θ d space (Å) Intensity (%)  6.97 ± 0.20 12.677 ± 0.363  1513.24 ± 0.20 6.683 ± 0.101 13 14.39 ± 0.20 6.150 ± 0.085 21 17.74 ± 0.204.994 ± 0.056 100 17.98 ± 0.20 4.929 ± 0.054 27 18.03 ± 0.20 4.915 ±0.054 24 19.85 ± 0.20 4.470 ± 0.045 47 21.32 ± 0.20 4.164 ± 0.039 2322.60 ± 0.20 3.931 ± 0.034 95 23.68 ± 0.20 3.754 ± 0.031 25 26.52 ± 0.203.359 ± 0.025 34

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.177 Any of formulae 1.163-1.176 wherein the Crystalline Form C        exhibits an XRPD pattern comprising the 2-theta (°) values set        forth in Table H of formula 1.176, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.178 Any of formulae 1.163-1.177 wherein the Crystalline Form C        exhibits an XRPD pattern having representative 2-theta (°)        values as set forth in Table H of formula 1.176, wherein the        XRPD is measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.179 Any of formulae 1.163-1.178 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, e.g., at least        eleven, e.g., at least fifteen, e.g., at least twenty,        2-theta (0) values selected from the group consisting of 7.0,        13.2, 13.7, 14.0, 14.4, 16.3, 17.7, 18.0, 18.3, 19.9, 21.1,        21.3, 22.6, 23.4, 23.7, 23.9, 26.0, 26.5, 26.7, 26.9, 27.4,        28.0, 28.2, 29.1, and 29.5, wherein the XRPD is measured using        an incident beam of Cu radiation, e.g., Cu Kα radiation, e.g.,        wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.180 Any of formulae 1.163-1.179 wherein the Crystalline Form C        exhibits an XRPD pattern comprising the following 2-theta (°)        values: 7.0, 13.2, 13.7, 14.0, 14.4, 16.3, 17.7, 18.0, 18.3,        19.9, 21.1, 21.3, 22.6, 23.4, 23.7, 23.9, 26.0, 26.5, 26.7,        26.9, 27.4, 28.0, 28.2, 29.1, and 29.5, wherein the XRPD is        measured using an incident beam of Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å.    -   1.181 Any of formulae 1.163-1.180 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, e.g., at least        eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at        least twenty-five, 2-theta (°) values selected from the group        consisting of 6.97, 13.24, 13.68, 13.97, 14.39, 16.29, 17.74,        17.98, 18.03, 18.30, 19.85, 21.06, 21.32, 22.60, 23.35, 23.68,        23.94, 25.99, 26.52, 26.66, 26.90, 27.40, 27.99, 28.19, 29.06,        and 29.52, wherein the XRPD is measured using an incident beam        of Cu radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD        is measured using radiation of wavelength 1.54059 Å.    -   1.182 Any of formulae 1.163-1.181 wherein the Crystalline Form C        exhibits an XRPD pattern comprising the following 2-theta (°)        values: 6.97, 13.24, 13.68, 13.97, 14.39, 16.29, 17.74, 17.98,        18.03, 18.30, 19.85, 21.06, 21.32, 22.60, 23.35, 23.68, 23.94,        25.99, 26.52, 26.66, 26.90, 27.40, 27.99, 28.19, 29.06, and        29.52, wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.183 Any of formulae 1.163-1.182 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, e.g., at least        eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at        least twenty-five, 2-theta (°) values selected from those set        forth in Table I below:

TABLE I °2θ d space (Å) Intensity (%)  6.97 ± 0.20 12.677 ± 0.363  1513.24 ± 0.20 6.683 ± 0.101 13 13.68 ± 0.20 6.469 ± 0.094 2 13.97 ± 0.206.333 ± 0.090 3 14.39 ± 0.20 6.150 ± 0.085 21 16.29 ± 0.20 5.435 ± 0.0666 17.74 ± 0.20 4.994 ± 0.056 100 17.98 ± 0.20 4.929 ± 0.054 27 18.03 ±0.20 4.915 ± 0.054 24 18.30 ± 0.20 4.843 ± 0.052 13 19.85 ± 0.20 4.470 ±0.045 47 21.06 ± 0.20 4.214 ± 0.040 6 21.32 ± 0.20 4.164 ± 0.039 2322.60 ± 0.20 3.931 ± 0.034 95 23.35 ± 0.20 3.806 ± 0.032 14 23.68 ± 0.203.754 ± 0.031 25 23.94 ± 0.20 3.714 ± 0.031 13 25.99 ± 0.20 3.426 ±0.026 14 26.52 ± 0.20 3.359 ± 0.025 34 26.66 ± 0.20 3.340 ± 0.025 1626.90 ± 0.20 3.311 ± 0.024 14 27.40 ± 0.20 3.252 ± 0.023 6 27.99 ± 0.203.185 ± 0.022 6 28.19 ± 0.20 3.163 ± 0.022 3 29.06 ± 0.20 3.070 ± 0.0215 29.52 ± 0.20 3.024 ± 0.020 7

-   -   wherein the XRPD is measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.54059 Å.    -   1.184 Any of formulae 1.163-1.183 wherein the Crystalline Form C        exhibits an XRPD pattern comprising the 2-theta (0) values set        forth in Table I of formula 1.183, wherein the XRPD is measured        using an incident beam of Cu radiation, e.g., Cu Kα radiation,        e.g., wherein the XRPD is measured using radiation of wavelength        1.54059 Å.    -   1.185 Any of formulae 1.163-1.184 wherein the Crystalline Form C        exhibits an XRPD pattern comprising a d-spacing (A) value of        5.0.    -   1.186 Any of formulae 1.163-1.185 wherein the Crystalline Form C        exhibits an XRPD pattern comprising a d-spacing (A) value of        4.99.    -   1.187 Any of formulae 1.163-1.186 wherein the Crystalline Form C        exhibits an XRPD pattern comprising a d-spacing (A) value of        4.994.    -   1.188 Any of formulae 1.163-1.187 wherein the Crystalline Form C        exhibits an XRPD pattern comprising a d-spacing (A) value in        Table G of formula 1.168.    -   1.189 Any of formulae 1.163-1.188 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, d-spacing (A) values selected from        the group consisting of 12.7, 6.7, 6.2, 5.0, 4.9, 4.5, 4.2, 3.9,        3.8, and 3.4.    -   1.190 Any of formulae 1.163-1.189 wherein the Crystalline Form C        exhibits an XRPD pattern comprising d-spacing (A) values of        12.7, 6.7, 6.2, 5.0, 4.9, 4.5, 4.2, 3.9, 3.8, and 3.4.    -   1.191 Any of formulae 1.163-1.190 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, d-spacing (A)        values selected from the group consisting of 12.68, 6.68, 6.15,        4.99, 4.93, 4.92, 4.47, 4.16, 3.93, 3.75, and 3.36.    -   1.192 Any of formulae 1.163-1.191 wherein the Crystalline Form C        exhibits an XRPD pattern comprising d-spacing (A) values of        12.68, 6.68, 6.15, 4.99, 4.93, 4.92, 4.47, 4.16, 3.93, 3.75, and        3.36.    -   1.193 Any of formulae 1.163-1.192 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, d-spacing (A)        values selected from the group consisting of 12.677, 6.683,        6.150, 4.994, 4.929, 4.915, 4.470, 4.164, 3.931, 3.754, and        3.359.    -   1.194 Any of formulae 1.163-1.193 wherein the Crystalline Form C        exhibits an XRPD pattern comprising d-spacing (A) values of        12.677, 6.683, 6.150, 4.994, 4.929, 4.915, 4.470, 4.164, 3.931,        3.754, and 3.359.    -   1.195 Any of formulae 1.163-1.194 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, d-spacing (A)        values selected from those set forth in Table H of formula        1.176.    -   1.196 Any of formulae 1.163-1.195 wherein the Crystalline Form C        exhibits an XRPD pattern comprising the d-spacing (A) values set        forth in Table H of formula 1.176.    -   1.197 Any of formulae 1.163-1.196 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, e.g., at least        eleven, e.g., at least fifteen, d-spacing (A) values selected        from the group consisting of 12.7, 6.7, 6.5, 6.3, 6.2, 5.4, 5.0,        4.9, 4.8, 4.5, 4.2, 3.9, 3.8, 3.7, 3.4, 3.3, 3.2, 3.1, and 3.0.    -   1.198 Any of formulae 1.163-1.197 wherein the Crystalline Form C        exhibits an XRPD pattern comprising d-spacing (A) values of        12.7, 6.7, 6.5, 6.3, 6.2, 5.4, 5.0, 4.9, 4.8, 4.5, 4.2, 3.9,        3.8, 3.7, 3.4, 3.3, 3.2, 3.1, and 3.0.    -   1.199 Any of formulae 1.163-1.198 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, e.g., at least        eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at        least twenty-five, d-spacing (A) values selected from the group        consisting of 12.68, 6.68, 6.47, 6.33, 6.15, 5.44, 4.99, 4.93,        4.92, 4.84, 4.47, 4.21, 4.16, 3.93, 3.81, 3.75, 3.71, 3.43,        3.36, 3.34, 3.31, 3.25, 3.19, 3.16, 3.07, and 3.02.    -   1.200 Any of formulae 1.163-1.199 wherein the Crystalline Form C        exhibits an XRPD pattern comprising d-spacing (A) values of        12.68, 6.68, 6.47, 6.33, 6.15, 5.44, 4.99, 4.93, 4.92, 4.84,        4.47, 4.21, 4.16, 3.93, 3.81, 3.75, 3.71, 3.43, 3.36, 3.34,        3.31, 3.25, 3.19, 3.16, 3.07, and 3.02.    -   1.201 Any of formulae 1.163-1.200 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, e.g., at least        eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at        least twenty-five, d-spacing (A) values selected from the group        consisting of 12.677, 6.683, 6.469, 6.333, 6.150, 5.435, 4.994,        4.929, 4.915, 4.843, 4.470, 4.214, 4.164, 3.931, 3.806, 3.754,        3.714, 3.426, 3.359, 3.340, 3.311, 3.252, 3.185, 3.163, 3.070,        and 3.024.    -   1.202 Any of formulae 1.163-1.201 wherein the Crystalline Form C        exhibits an XRPD pattern comprising d-spacing (A) values of        12.677, 6.683, 6.469, 6.333, 6.150, 5.435, 4.994, 4.929, 4.915,        4.843, 4.470, 4.214, 4.164, 3.931, 3.806, 3.754, 3.714, 3.426,        3.359, 3.340, 3.311, 3.252, 3.185, 3.163, 3.070, and 3.024.    -   1.203 Any of formulae 1.163-1.202 wherein the Crystalline Form C        exhibits an XRPD pattern comprising at least one, e.g., at least        three, e.g., at least five, e.g., at least ten, e.g., at least        eleven, e.g., at least fifteen, e.g., at least twenty, e.g., at        least twenty-five, d-spacing (A) values selected from those set        forth in Table I of formula 1.183.    -   1.204 Any of formulae 1.163-1.203 having an XRPD pattern        comprising the d-spacing (A) values set forth in Table I of        formula 1.183.    -   1.205 Any of formulae 1.163-1.204 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern comprising        characteristic peaks of the XRPD pattern shown in FIG. 9,        wherein the XRPD is measured using Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.541871 Å.    -   1.206 Any of formulae 1.163-1.205 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern comprising        representative peaks of the XRPD pattern shown in FIG. 9,        wherein the XRPD is measured using Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.541871 Å.    -   1.207 Any of formulae 1.163-1.206 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        three peaks, in some embodiments, five peaks, selected from        those shown in FIG. 9.    -   1.208 Any of formulae 1.163-1.207 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising at        least one peak, e.g., at least five peaks, e.g., at least eleven        peaks, e.g., at least fifteen peaks, e.g., at least twenty        peaks, e.g., at least twenty-five peaks, selected from those        shown in FIG. 9.    -   1.209 Any of formulae 1.163-1.208 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, substantially        as shown in FIG. 9.    -   1.210 Any of formulae 1.163-1.209 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, as shown in        FIG. 9.    -   1.211 Any of formulae 1.163-1.210 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern comprising        characteristic peaks of the XRPD pattern shown in FIG. 11,        wherein the XRPD is measured using Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å, , e.g., wherein XRPD pattern also        comprises peaks of Crystalline Form A (e.g., a mixture of        Crystalline Forms A and C).    -   1.212 Any of formulae 1.163-1.211 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern comprising        representative peaks of the XRPD pattern shown in FIG. 11,        wherein the XRPD is measured using Cu radiation, e.g., Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å, e.g., wherein XRPD pattern also comprises        peaks of Crystalline Form A (e.g., a mixture of Crystalline        Forms A and C).    -   1.213 Any of formulae 1.163-1.212 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray        powder diffraction pattern measured using an incident beam of Cu        Kα radiation, e.g., wherein the XRPD is measured using radiation        of wavelength 1.54059 Å, comprising three peaks, in some        embodiments, five peaks, selected from those shown in FIG. 11,        e.g., wherein XRPD pattern also comprises peaks of Crystalline        Form A (e.g., a mixture of Crystalline Forms A and C).    -   1.214 Any of formulae 1.163-1.213 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray        powder diffraction pattern measured using an incident beam of Cu        Kα radiation, e.g., wherein the XRPD is measured using radiation        of wavelength 1.54059 Å, comprising at least one peak, e.g., at        least five peaks, e.g., at least eleven peaks, e.g., at least        fifteen peaks, e.g., at least twenty peaks, e.g., at least        twenty-five peaks, selected from those shown in FIG. 11, e.g.,        wherein XRPD pattern also comprises peaks of Crystalline Form A        (e.g., a mixture of Crystalline Forms A and C).    -   1.215 Any of formulae 1.163-1.214 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray        powder diffraction pattern measured using an incident beam of Cu        Kα radiation, e.g., wherein the XRPD is measured using radiation        of wavelength 1.54059 Å, substantially as shown in FIG. 11,        e.g., wherein XRPD pattern also comprises peaks of Crystalline        Form A (e.g., a mixture of Crystalline Forms A and C).    -   1.216 Any of formulae 1.163-1.215 wherein the Crystalline Form C        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., a high-resolution X-ray        powder diffraction pattern measured using an incident beam of Cu        Kα radiation, e.g., wherein the XRPD is measured using radiation        of wavelength 1.54059 Å, as shown in FIG. 11, e.g., wherein XRPD        pattern also comprises peaks of Crystalline Form A (e.g., a        mixture of Crystalline Forms A and C).    -   1.217 Any of formulae 1.163-1.216 wherein the Crystalline Form C        exhibits an XRPD pattern comprising characteristic peaks of the        XRPD pattern as shown in any of FIGS. 11 and 43, e.g., FIG. 11,        e.g., FIG. 43, wherein the XRPD is measured using Cu radiation,        e.g., Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.218 Any of formulae 1.163-1.217 wherein the Crystalline Form C        exhibits an XRPD pattern comprising representative peaks of the        XRPD pattern as shown in any of FIGS. 11 and 43, e.g., FIG. 11,        e.g., FIG. 43, wherein the XRPD is measured using Cu radiation,        e.g., Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å.    -   1.219 Any of formulae 1.163-1.218 wherein the Crystalline Form C        exhibits an XRPD pattern, e.g., an X-ray powder diffraction        pattern measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., a high-resolution X-ray powder        diffraction pattern measured using an incident beam of Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å, comprising three peaks, in some        embodiments, five peaks, selected from those shown in any of        FIGS. 11 and 43, e.g., FIG. 11, e.g., FIG. 43.    -   1.220 Any of formulae 1.163-1.219 wherein the Crystalline Form C        exhibits an XRPD pattern, e.g., an X-ray powder diffraction        pattern measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., a high-resolution X-ray powder        diffraction pattern measured using an incident beam of Cu Kα        radiation, e.g., wherein the XRPD is measured using radiation of        wavelength 1.54059 Å, comprising at least one peak, e.g., at        least five peaks, e.g., at least ten peaks, e.g., at least        eleven peaks, e.g., at least fifteen peaks, e.g., at least        twenty peaks, e.g., at least twenty-five peaks, selected from        those shown in any of FIGS. 11 and 43, e.g., FIG. 11, e.g., FIG.        43.    -   1.221 Any of formulae 1.163-1.220 wherein the Crystalline Form C        exhibits an XRPD pattern, e.g., an X-ray powder diffraction        pattern measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å, substantially as shown in any        of FIGS. 11 and 43, e.g., FIG. 11, e.g., FIG. 43.    -   1.222 Any of formulae 1.163-1.221 wherein the Crystalline Form C        exhibits an XRPD pattern, e.g., an X-ray powder diffraction        pattern measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.54059 Å, as shown in any of FIGS. 11        and 43, e.g., FIG. 11, e.g., FIG. 43.    -   1.223 Any of formulae 1.163-1.222 wherein the Crystalline Form C        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak between 247° C. and 248° C.,        e.g., between 247° C. and 248° C. with an onset at 246° C.    -   1.224 Any of formulae 1.163-1.223 wherein the Crystalline Form C        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 247° C., e.g., an endothermic        peak at 247° C. with an onset at 246° C.    -   1.225 Any of formulae 1.163-1.224 wherein the Crystalline Form C        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 248° C., e.g., an endothermic        peak at 248° C. with an onset at 246° C.    -   1.226 Any of formulae 1.163-1.225 wherein the Crystalline Form C        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 122° C., e.g, an endothermic        peak at 122° C. with an onset at 112° C.    -   1.227 Any of formulae 1.163-1.226 wherein the Crystalline Form C        exhibits a differential scanning calorimetry (DSC) thermogram        comprising an endothermic peak at 271° C.    -   1.228 Any of formulae 1.163-1.227 wherein the Crystalline Form C        exhibits a differential scanning calorimetry (DSC) thermogram as        shown in FIG. 12.    -   1.229 Any of formulae 1.163-1.228 wherein the Crystalline Form C        exhibits a thermogravimetric analysis (TGA) comprising 1.3%        weight loss up to 200° C.    -   1.230 Any of formulae 1.163-1.229 wherein the Crystalline Form C        exhibits a thermogravimetric analysis (TGA) thermogram        comprising an onset decomposition temperature at 266° C.    -   1.231 Any of formulae 1.163-1.230 wherein the Crystalline Form C        exhibits a thermogravimetric analysis (TGA) thermogram as shown        in FIG. 12.    -   1.232 Å Crystalline Form of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride as described and/or made as in any of the        examples.    -   1.233 Å Crystalline Form of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride having an X-ray powder diffraction and/or X-ray        crystal structure as depicted in any of the Figures.    -   1.234 The Crystalline Form of any of formulae 1.1-1.233 wherein        the XRPD pattern is measured using a copper source, e.g., a        copper anode.    -   1.235 Å combination of any of the Crystalline Forms A through F,        e.g., any of formulae 1.1-1.234 and any of formulae 2.1-2.25,        e.g., a combination of Crystalline Form A and Crystalline Form        B; a combination of Crystalline Form A and Crystalline Form C; a        combination of Crystalline Form A, Crystalline Form B, and        Crystalline Form C; a combination of Crystalline Form B and        Crystalline Form C; a combination of Crystalline Form B and        Crystalline Form D; a combination of Crystalline Form E and        Crystalline Form F.    -   1.236 The Crystalline Form according to any of formulae        1.1-1.234, e.g., Crystalline Form A, e.g., any of formulae        1.1-1.77, e.g., Crystalline Form B, e.g., any of formulae        1.78-1.162, wherein said Crystalline Form is free or        substantially free of any other form, e.g., less than 20 wt. %,        e.g., less than 15 wt. %, e.g., less than 10 wt. %, preferably        less than 5 wt. %, preferably less than 3 wt. %, more preferably        less than 2 wt. %, still preferably less than 1 wt. %, still        preferably less than 0.1 wt. %, most preferably less than 0.01        wt. %, of the amorphous form.    -   1.237 The Crystalline Form according to any of formulae        1.1-1.234, e.g., Crystalline Form A, e.g., any of formulae        1.1-1.77, e.g., Crystalline Form B, e.g., any of formulae        1.78-1.162, wherein said Crystalline Form is free or        substantially free of any other form, e.g., less than 20 wt. %,        e.g., less than 10 wt. %, preferably less than 5 wt. %,        preferably less than 3 wt. %, more preferably less than 2 wt. %,        still preferably less than 1 wt. %, still preferably less than        0.1 wt. %, most preferably less than 0.01 wt. %, of any other        crystalline form.    -   1.238 The Crystalline Form according to any of formulae        1.1-1.234, e.g., Crystalline Form A, e.g., any of formulae        1.1-1.77, e.g., Crystalline Form B, e.g., any of formulae        1.78-1.162, wherein said Crystalline Form is free or        substantially free of any other form, e.g., less than 20 wt. %,        e.g., less than 10 wt. %, preferably less than 5 wt. %,        preferably less than 3 wt. %, more preferably less than 2 wt. %,        still preferably less than 1 wt. %, still preferably less than        0.1 wt. %, most preferably less than 0.01 wt. %, of the        amorphous form and any other crystalline form.    -   1.239 The Crystalline Form according to any of formulae        1.1-1.238 when made by any of processes described in formula        4.1-4.20 or similarly described in any of the examples or having        an X-ray powder diffraction or X-ray crystal structure as        depicted in any of the Figures.

In the second aspect, the invention provides a citrate salt of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane.

In the third aspect, the invention provides a phosphate salt of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane.

In the fourth aspect, the invention provides a crystalline form as madeor described in any of the examples or having an X-ray powderdiffraction as depicted in any of the Figures, e.g.:

-   -   2.1 Crystalline Form D.    -   2.2 Formula 2.1 wherein the Crystalline Form D exhibits an X-ray        powder diffraction pattern, e.g., an X-ray powder diffraction        pattern measured using an incident beam of Cu radiation, e.g.,        Cu Kα radiation, e.g., wherein the XRPD is measured using        radiation of wavelength 1.541871 Å, comprising characteristic        peaks of the XRPD pattern shown in FIG. 15.    -   2.3 Formula 2.1 or 2.2 wherein the Crystalline Form D exhibits        an X-ray powder diffraction pattern, e.g., an X-ray powder        diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        representative peaks of the XRPD pattern shown in FIG. 15.    -   2.4 Any of formula 2.1-2.3 wherein the Crystalline Form D        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        three peaks, in some embodiments, five peaks, selected from        those shown in FIG. 15.    -   2.5 Any of formula 2.1-2.4 wherein the Crystalline Form D        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        ten peaks, in some embodiments twenty peaks, in some embodiments        twenty-five peaks, selected from those shown in FIG. 15.    -   2.6 Any of formula 2.1-2.5 wherein the Crystalline Form D        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, substantially        as shown in FIG. 15.    -   2.7 Any of formulae 2.1-2.6 wherein the Crystalline Form D        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, as shown in        FIG. 15.    -   2.8 Any of formulae 2.1-2.7 wherein the Crystalline Form D is a        citrate salt of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. 2.9        Crystalline Form E.    -   2.10 Formula 2.9 wherein the Crystalline Form E exhibits an        X-ray powder diffraction pattern, e.g., an X-ray powder        diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        characteristic peaks of the XRPD pattern shown in FIG. 16.    -   2.11 Formula 2.9 or 2.10 wherein the Crystalline Form E exhibits        an X-ray powder diffraction pattern, e.g., an X-ray powder        diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        representative peaks of the XRPD pattern shown in FIG. 16.    -   2.12 Any of formula 2.9-2.11 wherein the Crystalline Form E        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        three peaks, in some embodiments, five peaks, selected from        those shown in FIG. 16.    -   2.13 Any of formula 2.9-2.12 wherein the Crystalline Form E        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        ten peaks, in some embodiments twenty peaks, in some embodiments        twenty-five peaks, selected from those shown in FIG. 16.    -   2.14 Any of formula 2.9-2.13 wherein the Crystalline Form E        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, substantially        as shown in FIG. 16.    -   2.15 Any of formulae 2.9-2.14 wherein the Crystalline Form E        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, as shown in        FIG. 16.    -   2.16 Any of formulae 2.9-2.15 wherein the Crystalline Form E is        a phosphate salt of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane.    -   2.17 Crystalline Form F.    -   2.18 Formula 2.17 wherein the Crystalline Form F exhibits an        X-ray powder diffraction pattern, e.g., an X-ray powder        diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        characteristic peaks of the XRPD pattern shown in FIG. 17.    -   2.19 Formula 2.17 or 2.18 wherein the Crystalline Form F        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        representative peaks of the XRPD pattern shown in FIG. 17.    -   2.20 Any of formula 2.17-2.19 wherein the Crystalline Form F        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        three peaks, in some embodiments, five peaks, selected from        those shown in FIG. 17.    -   2.21 Any of formula 2.17-2.20 wherein the Crystalline Form F        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, comprising        ten peaks, in some embodiments twenty peaks, in some embodiments        twenty-five peaks, selected from those shown in FIG. 17.    -   2.22 Any of formula 2.17-2.21 wherein the Crystalline Form F        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, substantially        as shown in FIG. 17.    -   2.23 Any of formulae 2.17-2.22 wherein the Crystalline Form F        exhibits an X-ray powder diffraction pattern, e.g., an X-ray        powder diffraction pattern measured using an incident beam of Cu        radiation, e.g., Cu Kα radiation, e.g., wherein the XRPD is        measured using radiation of wavelength 1.541871 Å, as shown in        FIG. 17.    -   2.24 Any of formulae 2.17-2.23 wherein the Crystalline Form F is        a phosphate salt of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane.    -   2.25 The Crystalline Form of any of formulae 2.1-2.24 wherein        the XRPD pattern is measured using a copper source, e.g., a        copper anode.    -   2.26 A combination of any of the Crystalline Forms A through F,        e.g., any of formulae 1.1-1.234 and any of formulae 2.1-2.25,        e.g., a combination of Crystalline Form A and Crystalline Form        B; a combination of Crystalline Form A and Crystalline Form C; a        combination of Crystalline Form A, Crystalline Form B, and        Crystalline Form C; a combination of Crystalline Form B and        Crystalline Form C; a combination of Crystalline Form B and        Crystalline Form D; a combination of Crystalline Form E and        Crystalline Form F.    -   2.27 The Crystalline Form according to any of formulae 2.1-2.25,        wherein said Crystalline Form is free or substantially free of        any other form, e.g., less than 20 wt. %, e.g., less than 15 wt.        %, e.g., less than 10 wt. %, preferably less than 5 wt. %,        preferably less than 3 wt. %, more preferably less than 2 wt. %,        still preferably less than 1 wt. %, still preferably less than        0.1 wt. %, most preferably less than 0.01 wt. %, of the        amorphous form.    -   2.28 The Crystalline Form according to any of formulae 2.1-2.25,        wherein said Crystalline Form is free or substantially free of        any other form, e.g., less than 20 wt. %, e.g., less than 10 wt.        %, preferably less than 5 wt. %, preferably less than 3 wt. %,        more preferably less than 2 wt. %, still preferably less than 1        wt. %, still preferably less than 0.1 wt. %, most preferably        less than 0.01 wt. %, of any other crystalline form.    -   2.29 The Crystalline Form according to any of formulae 2.1-2.25,        wherein said Crystalline Form is free or substantially free of        any other form, e.g., less than 20 wt. %, e.g., less than 10 wt.        %, preferably less than 5 wt. %, preferably less than 3 wt. %,        more preferably less than 2 wt. %, still preferably less than 1        wt. %, still preferably less than 0.1 wt. %, most preferably        less than 0.01 wt. %, of the amorphous form and any other        crystalline form.    -   2.30 The Crystalline Form according to any of formulae 2.1-2.29        when made by any of processes described in formula 4.1-4.20 or        similarly described in any of the examples or having an X-ray        powder diffraction or X-ray crystal structure as depicted in any        of the Figures.

Phase transitions of solids can be thermodynamically reversible orirreversible. Crystalline forms that transform reversibly at a specifictransition temperature (T_(t)) are enantiotropic polymorphs. If thecrystalline forms are not interconvertible under these conditions, thesystem is monotropic (one thermodynamically stable form).

Crystalline Forms A, B, and C are anhydrous enantiotropes of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.Crystalline Form C is the stable solid phase below the transitiontemperature T_(t,C→B), Crystalline Form B is the stable solid phasebetween T_(t,C→B) and T_(t,B→A), and Crystalline Form A is the stablesolid phase above T_(t,B→A). T_(t,C→B) is expected below 2° C. T_(t,C→A)will be between 2° C. and ambient temperature, and T_(t,B→A) is between37 and 54° C.

Owing to kinetic constraints, the thermodynamic transformation ofCrystalline Form A to Crystalline Form B is hindered. Therefore,surprisingly, Crystalline Form A appears to be sufficiently kineticallystable so as to persist in the solid state under temperature conditionswhere it is thermodynamically metastable.

Agitating Crystalline Form A as a slurry for 16 days in dichloromethaneat ambient temperature (see Example 6a) does not cause a solventmediated form conversion to Crystalline Form B, the more stable form atthat temperature. This indicates that the critical free energy barrierfor nucleation is not overcome in the absence of seeds of the morestable polymorph within the time frame evaluated.

Under exposure to accelerated stress conditions for two weeks,Crystalline Forms A and B remain unchanged at 30° C./56% RH or 40°C./75% RH (Example 11). In contrast, Crystalline Form C converts to amixture of Crystalline Forms A and B within two weeks at 40° C./75% RH(Example 11). Thus, unlike Crystalline Form A, Crystalline Form Cconverts under conditions in which it is metastable.

For Crystalline Form A, in the absence of seeds of the more stablepolymorph, the critical free energy barrier for the nucleation ofCrystalline Form B is not overcome in the solid state or in solventmediated conversion experiments within the time evaluated.

Thus, Crystalline Form A may be synthesized on large scale easily, yet,also, surprisingly, persists in the solid state even under conditions inwhich it is thermodynamically metastable.

In the fifth aspect, the invention provides the following:

-   -   3.1. A pharmaceutical composition comprising any of the        Crystalline Form A through F according to any of formulae        1.1-1.239 or 2.1-2.30, e.g., Crystalline Form A, e.g., any of        formulae 1.1-1.77, e.g., Crystalline Form B, e.g., any of        formulae 1.78-1.162, and a pharmaceutically acceptable diluent        or carrier.    -   3.2. The pharmaceutical composition according to formula 3.1,        wherein the composition is sustained release.    -   3.3. The pharmaceutical composition according to formula 3.1 or        3.2, comprising 1 mg to 1800 mg, e.g., 10 mg to 1800 mg, e.g.,        25 mg to 1800 mg, e.g., 10 mg to 1600 mg, e.g., 10 mg to 1200        mg, e.g., 50 mg to 1200 mg, e.g., 50 mg to 1000 mg, e.g., 75 mg        to 1000 mg, e.g., 75 mg to 800 mg, e.g., 75 mg to 500 mg, e.g.,        100 mg to 750 mg, e.g., 100 mg to 500 mg, e.g., 100 mg to 400        mg, e.g., 100 mg to 300 mg, e.g., 100 mg to 200 mg, of any of        the Crystalline Form A through F of the invention, e.g., any of        formulae 1.1-1.239, e.g., Crystalline Form A, e.g., any of        formulae 1.1-1.77, e.g., Crystalline Form B, e.g., any of        formulae 1.78-1.162, e.g., any of formulae 2.1-2.30.    -   3.4. The composition of any one of formulae 3.1-3.3 comprising        75 mg to 1000 mg, e.g., 100 mg to 600 mg, e.g., 100 mg to 400        mg, e.g., 100 mg to 200 mg, of any of the Crystalline Form A        through F of the invention, e.g., any of formulae 1.1-1.239,        e.g., Crystalline Form A, e.g., any of formulae 1.1-1.77, e.g.,        Crystalline Form B, e.g., any of formulae 1.78-1.162, e.g., any        of formulae 2.1-2.30.    -   3.5. The composition of any one of formulae 3.1-3.3 comprising        50 mg to 600 mg, e.g., 100 mg to 600 mg, e.g., 100 mg to 400 mg,        e.g., 100 mg to 200 mg, of any of the Crystalline Form A through        F of the invention, e.g., any of formulae 1.1-1.239, e.g.,        Crystalline Form A, e.g., any of formulae 1.1-1.77, e.g.,        Crystalline Form B, e.g., any of formulae 1.78-1.162, e.g., any        of formulae 2.1-2.30.    -   3.6. The composition of any one of formulae 3.1-3.3 comprising 5        mg to 500 mg, e.g., 5 mg to 10 mg, e.g., 10 mg to 25 mg, e.g.,        30 mg to 50 mg, e.g., 10 mg to 300 mg, e.g., 25 mg to 300 mg,        e.g., 50 mg to 100 mg, e.g., 100 mg to 250 mg, e.g., 250 mg to        500 mg, of any one of Crystalline Forms A through F of the        invention, e.g., e.g., any of formulae 1.1-1.239, e.g.,        Crystalline Form A, e.g., any of formulae 1.1-1.77, e.g.,        Crystalline Form B, e.g., any of formulae 1.78-1.162, e.g., any        of formulae 2.1-2.30.    -   3.7. The composition of any one of formulae 3.1-3.3 for        administration of 0.5 mg/kg to 20 mg/kg per day, e.g., 1 mg/kg        to 15 mg/kg per day, e.g., 1 mg/kg to 10 mg/kg per day, e.g., 2        mg/kg to 20 mg/kg per day, e.g., 2 mg/kg to 10 mg/kg per day,        e.g., 3 mg/kg to 15 mg/kg per day, of any of the Crystalline        Form A through F of the invention, e.g., any of formulae        1.1-1.239, e.g., Crystalline Form A, e.g., any of formulae        1.1-1.77, e.g., Crystalline Form B, e.g., any of formulae        1.78-1.162, e.g., any of formulae 2.1-2.30.    -   3.8. The composition of any one of formulae 3.1-3.7 comprising        less than 50% w/w of any one of Crystalline Forms A through F of        the invention, e.g., less than 40% w/w, e.g., less than 30% w/w,        less than 20% w/w, e.g., 1-40% w/w, e.g., 5-40% w/w, e.g.,        10-30% w/w, e.g., 15-25% w/w, e.g., 15-20% w/w, e.g., 17% w/w,        e.g., 25% w/w, e.g., any of formulae 1.1-1.239, e.g.,        Crystalline Form A, e.g., any of formulae 1.1-1.77, e.g.,        Crystalline Form B, e.g., any of formulae 1.78-1.162, e.g., any        of formulae 2.1-2.30.    -   3.9. The composition of any one of formulae 3.1-3.8 wherein the        pharmaceutically acceptable diluent or carrier comprises        hydroxypropyl methylcellulose.    -   3.10. The composition of formula 3.9, wherein the composition        comprises at least 10% w/w of the hydroxypropyl methylcellulose,        e.g., 10-50% w/w, e.g., 10-40% w/w, e.g., 20-50% w/w, e.g.,        20-40% w/w, e.g., 30-40% w/w, e.g., 37% w/w.    -   3.11. The composition of formula 3.9 or 3.10, wherein the degree        of methoxy substitution of the hydroxypropyl methylcellulose is        19-24%.    -   3.12. The composition of any one of formulae 3.9-3.11, wherein        the degree of hydroxypropoxy substitution of the hydroxypropyl        methylcellulose is 4-12%.    -   3.13. The composition of any one of formulae 3.9-3.12, wherein        the hydroxypropyl methylcellulose is hypromellose 2208.    -   3.14. The composition of any one of formulae 3.9-3.13, wherein        the hydroxypropyl methylcellulose has a nominal viscosity of        4,000 mPA·σ.    -   3.15. The composition of any one of formulae 3.9-3.13, wherein        the hydroxypropyl methylcellulose has a viscosity of 2,000-6,000        mPA·σ, e.g., 2,600 to 5,000 mPA, e.g., 2,663 to 4,970 mPA·σ.    -   3.16. The composition of any one of formulae 3.9-3.15, wherein        the pharmaceutically acceptable diluent or carrier comprises        alpha-lactose monohydrate.    -   3.17. The composition of formula 3.16, wherein the composition        comprises at least 10% w/w of the alpha-lactose monohydrate,        e.g., 10-80% w/w, e.g., 20-70% w/w, e.g., 20-60% w/w, e.g.,        20-50% w/w, e.g., 20-40% w/w, e.g., 20-30% w/w, e.g., 30-70%        w/w, e.g., 30-60% w/w, e.g., 30-50% w/w, e.g., 30%-40% w/w,        e.g., 37% w/w.    -   3.18. The composition of formula 3.16 or 3.17, wherein the        composition comprises milled alpha-lactose monohydrate.    -   3.19. The composition of any one of formulae 3.1-3.18, wherein        the composition comprises a co-processed mixture of        hydroxypropyl methylcellulose and alpha-lactose monohydrate        (e.g., Retalac®).    -   3.20. The composition of formula 3.19, wherein the mixture        comprises equal parts of the hydroxypropyl methylcellulose and        alpha-lactose monohydrate.    -   3.21. The composition of formula 3.19 or 3.20, wherein the        mixture comprises particles of hydroxypropyl methylcellulose and        alpha-lactose monohydrate with d₅₀ (median diameter) in the        range of 100 μm to 200 μm, e.g., 125 μm.    -   3.22. The composition of any one of formulae 3.19-3.21, wherein        the mixture comprises particles of hydroxypropyl methylcellulose        and alpha-lactose monohydrate wherein the particle size        distribution is as follows:    -   <63 μm≤25%    -   <100 μm: 35%    -   <250 m≥80%.    -   3.23. The composition of any one of formulae 3.19-3.22, wherein        the composition comprises at least 20% w/w of the mixture, e.g.,        at least 30% w/w, e.g., at least 40% w/w, e.g., at least 50%        w/w, e.g., at least 60% w/w, e.g., at least 70% w/w, e.g, at        least 80% w/w, e.g., 20-90% w/w, e.g., 30-80% w/w, e.g., 40-80%        w/w, e.g., 50-80% w/w, e.g., 60-80% w/w, e.g., 70-80% w/w, e.g.,        75% w/w.    -   3.24. The composition of any one of formulae 3.1-3.23, wherein        the pharmaceutically acceptable diluent or carrier comprises a        lubricant, e.g., magnesium stearate.    -   3.25. The composition of formula 3.24, wherein the lubricant is        one or more of glyceryl behenate, magnesium stearate, talc, and        sodium stearyl fumarate, e.g, magnesium stearate.    -   3.26. The composition of formula 3.24 or 3.25, wherein the        composition comprises less than 10% w/w of the lubricant, e.g.,        less than 5% w/w, less than 3% w/w, less than 1% w/w, e.g., 0.1        to 1% w/w, e.g., 0.1 to 0.8% w/w, e.g., 0.5% w/w.    -   3.27. The composition of any one of formulae 3.24-3.26, wherein        the composition comprises less than 10% w/w of magnesium        stearate, e.g., less than 5% w/w, less than 3% w/w, less than 1%        w/w, e.g., 0.1 to 1% w/w, e.g., 0.1 to 0.8% w/w, e.g., 0.5% w/w.    -   3.28. The composition of any one of formulae 3.1-3.27, wherein        the pharmaceutically acceptable diluent or carrier comprises one        or more of a diluent, disintegrant, binder, and modified release        agent.    -   3.29. The composition of formula 3.28, wherein the diluent is        one or more of mannitol (e.g., Pearlitol 300 DC),        micro-crystalline cellulose (e.g., Avicel pH 102), and        pre-gelatinized starch (e.g., Starch 1500).    -   3.30. The composition of formula 3.29, wherein the disintegrant        is one or both of crospovidone (e.g., Polyplasdone XL-10) and        sodium starch glycolate (e.g., Explotab).    -   3.31. The composition of formula 3.28, wherein the binder is        polyvinylpyrrolidone (e.g., Povidone K29/32).    -   3.32. The composition of formula 3.28, wherein the modified        release agent is one or more of hydroxypropyl cellulose (e.g.,        Klucel EXF, Klucel MXF, and/or Klucel HXF) and hydroxypropyl        methylcellulose (e.g., Methocel K100M, Methocel K4M PREM,        Methocel K15M PREM CR).    -   3.33. The composition of formula 3.28 or 3.32, wherein the        composition comprises at least 5% w/w of the modified release        agent, e.g., 5-60% w/w, e.g., 10-50% w/w, e.g., 10-40% w/w.    -   3.34. The composition of formula 3.32 or 3.33, wherein the        modified release agent is hydroxypropyl methylcellulose.    -   3.35. A method for the prophylaxis or treatment of a disorder        and/or alleviation of associated symptoms of any disorder        treatable by inhibiting reuptake of multiple biogenic amines        causally linked to the targeted CNS disorder, wherein the        biogenic amines targeted for reuptake inhibition are selected        from norepinephrine, and/or serotonin, and/or dopamine, in a        particular embodiment, a method for the prophylaxis or treatment        of any of the following disorders:        -   (i) attention deficit hyperactivity disorder (ADHD, both            pediatric and adult) and related behavioral disorders, as            well as forms and symptoms of alcohol abuse, drug abuse,            obsessive compulsive disorder, learning disorders, reading            problems, gambling addiction, manic symptoms, phobias, panic            attacks, oppositional defiant disorder, conduct disorder,            disruptive behavior disorder, academic problems in school,            smoking, abnormal sexual behaviors, schizoid behaviors,            somatization, depression (including but not limited to major            depressive disorder, recurrent; dysthymic disorder;            depressive disorder not otherwise specified (NOS); major            depressive disorder, single episode; depression associated            with bipolar disorder, Alzheimers, psychosis or Parkinson's            disease; postnatal depression; and seasonal affected            disorder), sleep disorders, generalized anxiety, stuttering,            and tic disorders (such as Tourette's syndrome);        -   (ii) ADHD, substance abuse, depression, anxiety disorders            (including but not limited to panic disorder, generalized            anxiety, obsessive compulsive disorder, post-traumatic            stress disorder, and social anxiety disorder), autism,            traumatic brain injury, cognitive impairment, schizophrenia            (particularly for cognition), obesity, chronic pain            disorders, personality disorder, and mild cognitive            impairment;        -   (iii) anxiety, panic disorder, posttraumatic stress            disorder, obsessive compulsive disorder, schizophrenia and            allied disorders, obesity, tic disorders, addiction,            Parkinson's disease, and chronic pain;        -   (iv) substance abuse disorders (including but not limited to            alcohol-related disorders, nicotine-related disorders,            amphetamine-related disorders, cannabis-related disorders,            cocaine-related disorders, hallucinogen-use disorders,            inhalant-related disorders, and opioid-related disorders);        -   (v) cognitive disorders, bipolar disorder, anorexia nervosa,            bulimia nervosa, cyclothymic disorder, chronic fatigue            syndrome, chronic or acute stress, fibromyalgia and other            somatoform disorders (including somatization disorder,            conversion disorder, pain disorder, hypochondriasis, body            dysmorphic disorder, undifferentiated somatoform disorder,            somatoform NOS), incontinence (i.e., stress incontinence,            genuine stress incontinence, and mixed incontinence),            inhalation disorders, mania, migraine headaches, peripheral            neuropathy;        -   (vi) addictive disorders (including but not limited to            eating disorders, impulse control disorders, alcohol-related            disorders, nicotine-related disorders, amphetamine-related            disorders, cannabis-related disorders, cocaine-related            disorders, hallucinogen use disorders, inhalant-related            disorders, opioid-related disorders);        -   (vii) fragile X-associated disorder;        -   (viii) autism spectrum disorder (ASD), e.g., in a patient            with a fragile X-associated disorder;        -   (ix) ADHD in a patient with a fragile X-associated disorder;        -   (x) co-morbid ADHD and depression;        -   (xi) co-morbid ADHD and substance abuse;        -   (xii) co-morbid ADHD and anxiety;        -   comprising administering to a patient in need thereof a            therapeutically effective amount of any of Crystalline Form            A through F according to any of formulae 1.1-1.239, e.g.,            Crystalline Form A, e.g., any of formulae 1.1-1.77, e.g.,            Crystalline Form B, e.g., any of formulae 1.78-1.162, e.g.,            any of formulae 2.1-2.30, or a pharmaceutical composition            according to any of formulae 3.1-3.34.    -   3.36. A pharmaceutical composition according to any of formulae        3.1-3.34 for use as a medicament, e.g., for use in the        manufacture of a medicament for the treatment or prophylaxis of        any of the disorders described in formula 3.35.    -   3.37. Crystalline Form A through F according to any of formulae        1.1-1.239, e.g., Crystalline Form A, e.g., any of formulae        1.1-1.77, e.g., Crystalline Form B, e.g., any of formulae        1.78-1.162, e.g., any of formulae 2.1-2.30, for use in the        prophylaxis or treatment of any of the disorders described in        formula 3.35, or for use in the manufacture of a medicament for        the treatment or prophylaxis of any of the disorders described        in formula 3.35.

In the sixth aspect, the invention provides the Crystalline Formaccording to any of formulae 1.1-1.239 or any of formulae 2.1-2.30 whenmade by any of the processes described or similarly described asfollows:

-   -   4.1 Adding water to the Compound in hydrochloric acid addition        salt form ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride);        -   heating to dissolve all solids, e.g., heating to an internal            temperature between 30-40° C., e.g., 34° C.;        -   adding an organic solvent, e.g., tetrahydrofuran and/or            isopropylacetate; separating aqueous layer;        -   adding base, e.g., aqueous ammonia, to the aqueous layer;        -   adding an organic solvent, e.g., isopropylacetate;        -   agitating, e.g., for a minimum of 15 minutes;        -   allowing layers to settle, e.g., for a minimum of 30            minutes;        -   separating organic layer;        -   drying organic layer, e.g., with magnesium sulphate;        -   filtering;        -   washing filtercake with an organic solvent, e.g.,            isopropylacetate;        -   concentrating filtrate and washes;        -   adding isopropyl alcohol;        -   stirring at room temperature to dissolve all solids;        -   adding hydrochloric acid, e.g., HCl in isopropanol, to form            solids, e.g., adding HCl over 10 minutes, e.g., adding HCl            in isopropanol over 10 minutes; adding additional            hydrochloric acid, e.g., HCl in isopropanol, e.g., adding            additional HCl over 55 minutes, e.g., adding HCl in            isopropanol over 55 minutes; stirring slurry, e.g., stirring            slurry for 35 minutes;        -   adding additional hydrochloric acid, e.g., HCl in            isopropanol, e.g., adding additional HCl over 10 minutes,            e.g., adding HCl in isopropanol over 10 minutes;        -   stirring slurry, e.g., stirring slurry for 30 minutes;        -   filtering;        -   washing filtercake with an organic solvent, e.g., isopropyl            alcohol; and drying filtercake.    -   4.2 Storing Crystalline Form A at 40° C./75% RH, e.g., storing        Crystalline Form A at 40° C./75% RH for 7 days; and isolating        crystals.    -   4.3 Preparing a solution of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A, e.g., in chloroform,        dichloromethane, hexafluoroisopropylalcohol, methanol, and/or        2,2,2,-trifluoroethanol (TFE); sonicating;        -   achieving complete dissolution as judged by visual            observation;        -   filtering;        -   evaporating at ambient conditions, e.g., in a vial covered            with aluminium foil perforated with pinholes; and isolating            crystals.    -   4.4 Preparing a solution of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A, e.g., in chloroform,        dichloromethane, ethanol, and/or methanol;        -   filtering;        -   admixing with antisolvent, e.g., toluene, heptane,            acetonitrile, methyl ethyl ketone, acetone, hexanes,            tetrahydrofuran, dioxane, ethyl acetate, and/or isopropyl            ether; and isolating crystals.    -   4.5 Exposing        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A, to vapor, e.g., organic        solvent vapor, e.g., dichloromethane and/or ethanol vapor; and        isolating crystals.    -   4.6 Preparing a suspension of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A, e.g., in        dichloromethane, ethanol, isopropyl alcohol, 1-propanol, and/or        water;        -   agitating at ambient temperature or elevated temperature;            and isolating crystals, e.g., by vacuum filtration.    -   4.7 Preparing a solution of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A, at elevated temperature        in an organic solvent, e.g., dichloromethane, ethanol, isopropyl        alcohol, and/or 1-propanol; filtering, e.g., through 0.2 μm        nylon filter, into a warm vial;        -   cooling;        -   optionally further cooling by placing in a refrigerator            and/or freezer; and isolating crystals.    -   4.8 Preparing a solution of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A, at elevated temperature        in an organic solvent, e.g., dichloromethane, ethanol, isopropyl        alcohol, and/or 1-propanol; filtering, e.g., through 0.2 μm        nylon filter, into a cooled vial;        -   cooling below 0° C., e.g., placing in −78° C. bath, e.g., an            isopropyl alcohol/dry ice bath;        -   optionally further cooling by placing in a freezer; and            isolating crystals.    -   4.9 Preparing a solution of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A in an organic solvent,        e.g., ethanol, isopropyl alcohol, methanol, acetone, toluene,        1-propanol, water, and/or dioxane; sonicating;        -   achieving complete dissolution as judged by visual            observation;        -   filtering, e.g., through 0.2 μm nylon filter;        -   evaporating at ambient temperature; and isolating crystals.    -   4.10 Preparing a solution or suspension of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A in an organic solvent,        e.g., dichloromethane, ethanol, isopropyl alcohol, and/or        1-propanol; cooling, e.g, in a freezer; and isolating crystals.    -   4.11 Preparing a solution or suspension of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride, e.g., Crystalline Form A in an organic solvent,        e.g., hexafluoroisopropyl alcohol and/or 2,2,2-trifluoroethanol;        filtering, e.g., through 0.2 μm nylon filter;        -   adding anti-solvent, e.g., an organic anti-solvent, e.g.,            isopropyl ether, tetrahydrofuran, acetonitrile, ethyl            acetate, and/or methyl ethyl ketone, until precipitation;            and        -   isolating crystals, e.g., by vacuum filtration.    -   4.12 Dissolving        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in an        organic solvent, e.g., isopropanol;        -   adding HCl, eg., HCl in isopropanol; and optionally            filtering.    -   4.13 Seeding a solution or slurry with crystals of the desired        form, e.g., seeding a solution or slurry with Crystalline Form        A, e.g., seeding while the temperature of the solution or slurry        is above room temperature, e.g., 65° C.    -   4.14 Dissolving a solution of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride in an organic solvent, e.g., ethanol, while        heating, e.g., to 70° C.; optionally filtering, e.g., via an        encapsulated carbon filter;        -   optionally concentrating, e.g., to 5 total volumes (relative            to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane            hydrochloride input);        -   optionally reheating to redissolve any solids;        -   optionally cooling, e.g., cooling to 65° C.;        -   seeding the solution;        -   optionally stirring to develop the seed bed;        -   optionally cooling; and optionally filtering.    -   4.15 Dissolving        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride in water, e.g., with heat, e.g., heating to an        internal temperature between 30-40° C., e.g., 34° C.;        -   washing the aqueous solution;        -   adding a base, e.g., ammonia;        -   extracting            (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane with            an organic solvent, e.g., isopropyl acetate;        -   optionally drying, e.g., over magnesium sulphate;        -   optionally concentrating to yield a solid;        -   optionally adding an organic solvent to dissolve the solid,            e.g., isopropanol; and adding HCl, e.g., HCl in isopropanol;        -   optionally filtering; and optionally washing with an organic            solvent, e.g., isopropanol.    -   4.16 Dissolving a solution of        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane        hydrochloride in an organic solvent, e.g., ethanol, while        heating, e.g., to 70° C.; optionally filtering, e.g., via an        encapsulated carbon filter;        -   concentrating, e.g., to 5 total volumes (relative to            (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane            hydrochloride input);        -   optionally seeding before or after concentrating; and            optionally filtering.    -   4.17 Dissolving        (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in an        organic solvent;        -   adding HCl, e.g., HCl in isopropanol; and optionally            filtering.    -   4.18 Any of processes 4.1-4.17 further comprising isolating the        Crystalline Form, e.g., any of formulae 1.1-1.239 or 2.1-2.30,        e.g., Crystalline Form A, e.g., any of formulae 1.1-1.77, e.g.        Crystalline Form B, e.g., any of formulae 1.78-1.162.    -   4.19 A Crystalline Form according to any of formulae 1.1-1.239        or 2.1-2.30 when made by any of Examples 1-3, e.g., Example 1.    -   4.20 A Crystalline Form according to any of formulae 1.1-1.239        or 2.1-2.30 when made by any of the syntheses described in the        Examples, e.g., Example 1, e.g., e.g., Example 3, e.g., any of        Examples 6-13, e.g., Example 17, e.g., Example 18.

In the seventh aspect, the invention provides a process for makingCrystalline Form A through F according to any of formulae 1.1-1.239 or2.1-2.30, e.g., Crystalline Form A, e.g., any of formulae 1.1-1.77,e.g., Crystalline Form B, e.g., any of formulae 1.78-1.162, by anyprocess described in any of formula 4.1-4.20 or described in any of theExamples.

In the eight aspect, the invention provides a process for making apharmaceutical composition comprising any of the Crystalline Form Athrough F according to any of formulae 1.1-1.239 or 2.1-2.30, e.g.,Crystalline Form A, e.g., any of formulae 1.1-1.77, e.g., CrystallineForm B, e.g., any of formulae 1.78-1.162, e.g., a pharmaceuticalcomposition according to any of formula 3.1-3.34, wherein the processcomprises:

isolating any of the Crystalline Form A through F according to any offormulae 1.1-1.239 or 2.1-2.30, e.g., Crystalline Form A, e.g., any offormulae 1.1-1.77, e.g., Crystalline Form B, e.g., any of formulae1.78-1.162, and

admixing the isolated Crystalline Form with a pharmaceuticallyacceptable diluent or carrier.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 depicts a high-resolution X-ray powder diffraction (XRPD) patternof Crystalline Form A.

FIG. 2 depicts DSC and TGA thermograms of Crystalline Form A.

FIG. 3 depicts dynamic vapor sorption/desorption isotherm of CrystallineForm A.

FIG. 4 depicts an overlay of X-ray powder diffraction (XRPD) patterns ofCrystalline Form A, Form B, and Form C (from top to bottom):

pattern labeled A depicts a high resolution X-ray powder diffractionpattern of Crystalline Form A;

pattern labeled B depicts an X-ray powder diffraction pattern ofCrystalline Form B; and

pattern labeled C depicts an X-ray powder diffraction pattern ofCrystalline Form C.

FIG. 5 depicts an X-ray powder diffraction (XRPD) pattern of CrystallineForm B.

FIG. 6 depicts an indexing solution for Crystalline Form B.

FIG. 7 depicts a high-resolution X-ray powder diffraction (XRPD) patternof Crystalline Form B.

FIG. 8 depicts DSC and TGA thermograms of Crystalline Form B.

FIG. 9 depicts an X-ray powder diffraction (XRPD) pattern of CrystallineForm C.

FIG. 10 depicts an indexing solution for Crystalline Form C.

FIG. 11 depicts a high-resolution X-ray powder diffraction (XRPD)pattern of Crystalline Form C.

FIG. 12 depicts DSC and TGA thermograms of Crystalline Form C.

FIG. 13 depicts an overlay of X-ray powder diffraction (XRPD) patternsof Crystalline Form A, Form B, and Form C (from top to bottom):

pattern labeled A depicts an X-ray powder diffraction pattern ofCrystalline Form B (slow cooling in IPA, solids precipitate inrefrigerator);

pattern labeled B depicts an X-ray powder diffraction pattern ofCrystalline Form C+Crystalline Form B (slow crystalline cooling in IPA,with seeds, solids precipitate in freezer);

pattern labeled C depicts an X-ray powder diffraction pattern ofCrystalline Form C+Crystalline Form A (slow cooling in IPA, solidsprecipitate in freezer);

pattern labeled D depicts an X-ray powder diffraction pattern ofCrystalline Form B (slow cooling in IPA, solids precipitate in freezer);

pattern labeled E depicts an X-ray powder diffraction pattern ofCrystalline Form B+Crystalline Form A (crash cooling in IPA, solidsprecipitate in dry ice/IPA);

pattern labeled F depicts an X-ray powder diffraction pattern ofCrystalline Form A+Crystalline Form C (slow cooling in IPA, solidsprecipitate in freezer); and

pattern labeled G depicts an X-ray powder diffraction pattern ofCrystalline Form C, slow cooling in IPA.

FIG. 14 depicts an overlay of X-ray powder diffraction (XRPD) patternsof Crystalline Form D, Form E, and Form F (from top to bottom):

pattern labeled D depicts an X-ray powder diffraction pattern ofCrystalline Form D (30-min stir at 70° C. in pH 4.4 buffer);

pattern labeled E depicts an X-ray powder diffraction pattern ofCrystalline Form E (contains peaks of Crystalline Form F, slurry at 50°C. in pH 6.0 buffer); and

pattern labeled F depicts an X-ray powder diffraction pattern ofCrystalline Form F (30-min stir at 70° C. in pH 8.1 buffer).

FIG. 15 depicts an X-ray powder diffraction (XRPD) pattern ofCrystalline Form D.

FIG. 16 depicts an X-ray powder diffraction (XRPD) pattern ofCrystalline Form E (contains peaks of Crystalline Form F).

FIG. 17 depicts an X-ray powder diffraction (XRPD) pattern ofCrystalline Form F.

FIG. 18 depicts an ORTEP drawing of Crystalline Form A. Atoms arerepresented by 50% probability anisotropic thermal ellipsoids.

FIG. 19 depicts a packing diagram of Crystalline Form A viewed down thecrystallographic a axis.

FIG. 20 depicts a packing diagram of Crystalline Form A viewed down thecrystallographic b axis.

FIG. 21 depicts a packing diagram of Crystalline Form A viewed down thecrystallographic c axis.

FIG. 22 depicts hydrogen bonding in Crystalline Form A.

FIG. 23 depicts a calculated X-ray powder diffraction (XRPD) pattern ofCrystalline Form A.

FIG. 24 depicts an atomic displacement ellipsoid drawing for CrystallineForm B (atoms are represented by 50% probability anisotropic thermalellipsoids).

FIG. 25 depicts a packing diagram of Crystalline Form B viewed along thecrystallographic a axis.

FIG. 26 depicts a packing diagram of Crystalline Form B viewed along thecrystallographic b axis.

FIG. 27 depicts a packing diagram of Crystalline Form B viewed along thecrystallographic c axis.

FIG. 28 depicts hydrogen bonding in the structure of Crystalline Form B.

FIG. 29 depicts the molecular conformations of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in the structuresof Crystalline Forms A and B (left:(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in the structureof Crystalline Form A; right:(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in the structureof Crystalline Form B).

FIG. 30 depicts a packing diagram of Crystalline Forms A and B viewedalong the crystallographic a axis (left: packing of Crystalline Form A;right: packing of Crystalline Form B).

FIG. 31 depicts hydrogen bonding in the structures of Crystalline FormsA and B (left: hydrogen bonding in the structure of Crystalline Form A;right: hydrogen bonding in the structure of Form B).

FIG. 32 depicts a calculated X-ray powder pattern of Crystalline Form B.

FIG. 33 depicts experimental and calculated XRPD patterns of CrystallineForm B (top: experimental XRPD pattern at room temperature; middle:calculated XRPD pattern adjusted to room temperature; bottom: calculatedXRPD pattern at 100 K).

FIG. 34 depicts experimental and calculated XRPD patterns of CrystallineForm A (top: calculated XRPD pattern; bottom: experimental XRPD patternat room temperature).

FIG. 35 depicts an XRPD pattern of Crystalline Form A.

FIG. 36 depicts an XRPD pattern comparison of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride fromExamples 1 and 5 (top: Example 5; bottom: Example 1) (patterns areoffset along the y-axis for comparison).

FIG. 37 depicts an XRPD pattern of Crystalline Form A collected with CuKα radiation.

FIG. 38 depicts an indexing result for the XRPD pattern depicted in FIG.37 collected with Cu Kα radiation.

FIG. 39 depicts observed peaks for the XRPD pattern depicted in FIG. 37collected with Cu Kα radiation.

FIG. 40 depicts an XRPD pattern of Crystalline Form B.

FIG. 41 depicts an indexing result for the XRPD pattern depicted in FIG.40 collected with Cu Kα radiation.

FIG. 42 depicts observed peaks for the XRPD pattern depicted in FIG. 40collected with Cu Kα radiation.

FIG. 43 depicts an XRPD pattern of Crystalline Form C.

FIG. 44 depicts an indexing result for the XRPD pattern depicted in FIG.43 collected with Cu Kα radiation.

FIG. 45 depicts observed peaks for the XRPD pattern depicted in FIG. 43collected with Cu Kα radiation.

FIG. 46 depicts proposed energy-temperature plots for Crystalline FormsA, B, and C.

FIG. 47 depicts an XRPD pattern of Crystalline Form A.

FIG. 48 depicts an XRPD pattern of Crystalline Form B.

FIG. 49 depicts an XRPD pattern of a mixture of Crystalline Form A and aminor quantity of Crystalline Form B.

FIG. 50 depicts XRPD patterns of Crystalline Form A before and after DVSanalysis (top: before, bottom: after).

FIGS. 51-54 depict XRPD patterns of disordered Crystalline Form A.

FIG. 55 depicts a DSC Thermogram of Crystalline Form B.

FIG. 56 depicts an XRPD pattern of a mixture of Crystalline Forms A andB.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, the term “the Compound” refers to(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane. The term “theCompound in hydrochloric acid addition salt form” refers to(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride or(+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride havingthe following structure:

This compound is free or substantially free of the corresponding(−)-enantiomer, e.g., containing no more than 20% w/w (weight/weight) ofthe corresponding (−) enantiomer, in free or pharmaceutically acceptablesalt form, e.g., no more than 10% w/w of the corresponding (−)enantiomer, in free or pharmaceutically acceptable salt form, e.g., nomore than 5% w/w of the corresponding (−) enantiomer, in free orpharmaceutically acceptable salt form, e.g., no more than 2% w/w of thecorresponding (−) enantiomer, in free or pharmaceutically acceptablesalt form, e.g., no more than 1% w/w of the corresponding (−)enantiomer, in free or pharmaceutically acceptable salt form.

“Crystalline Form A” refers to a crystalline form of the Compound inhydrochloric acid addition salt form as described in any of formulae1.1-1.77 or as characterized in relevant sections of the Examples below.

“Crystalline Form B” refers to a crystalline form of the Compound inhydrochloric acid addition salt form as described in any of formulae1.78-1.162 or as characterized in relevant sections of the Examplesbelow.

“Crystalline Form C” refers to a crystalline form of the Compound inhydrochloric acid addition salt form as described in any of formulae1.163-1.231 or as characterized in relevant sections of the Examplesbelow.

“Crystalline Form D” refers to a crystalline form as described in any offormulae 2.1-2.8 or as characterized in relevant sections of theExamples below.

“Crystalline Form E” refers to a crystalline form as described in any offormulae 2.9-2.16 or as characterized in relevant sections of theExamples below.

“Crystalline Form F” refers to a crystalline form as described in any offormulae 2.17-2.24 or as characterized in relevant sections of theExamples below.

The invention claims Crystalline Form A through F and combinationsthereof as described herein, for example in any of formulae 1.1-1.239 orin any of formulae 2.1-2.30. These Crystalline Forms can be made andcharacterized as set forth in the Example section below. Therefore, theinvention provides any of Crystalline Form A through F as set forth inany of formulae 1.1-1.239 or in any of formulae 2.1-2.30 or ascharacterized in the Example section below.

The term “substantially free” of other crystalline forms refer to lessthan 10 wt. %, in some embodiments less than 5 wt. %, in someembodiments less than 2 wt. %, still in some embodiments less than 1 wt.%, still in some embodiments less than 0.1 wt. %, yet in someembodiments less than 0.01 wt. % of other forms or other crystal forms,e.g., amorphous or other crystal forms.

The term “solvate” refers to crystalline solid adducts containing eitherstoichiometric or nonstoichiometric amounts of a solvent incorporatedwithin the crystal structure. Therefore, the term “non-solvate” formherein refers to crystalline forms that are free or substantially freeof solvent molecules within the crystal structures of the invention.Similarly, the term “non-hydrate” form herein refers to salt crystalsthat are free or substantially free of water molecules within thecrystal structures of the invention.

The term “amorphous” form refers to solids of disordered arrangements ofmolecules and do not possess a distinguishable crystal lattice.

The term “patient” includes human and non-human. In one embodiment, thepatient is a human. In another embodiment, the patient is a non-human.

The term “anti-solvent” means a solvent in which the Compound and/or theCompound in hydrochloric acid addition salt form((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride)has low solubility or is insoluble. For instance, an anti-solventincludes a solvent in which the Compound and/or the Compound inhydrochloric acid addition salt form has a solubility of less than 35mg/ml, e.g., a solubility of 10-30 mg/ml, e.g., a solubility of 1-10mg/ml, e.g., a solubility of less than 1 mg/ml.

The term “XRPD” means X-ray powder diffraction.

It is to be understood that an X-ray powder diffraction pattern of agiven sample may vary (standard deviation) depending on the instrumentused, the time and temperature of the sample when measured, and standardexperimental errors. Therefore, the 2-theta values, d-spacing values,heights and relative intensity of the peaks will have an acceptablelevel of deviation. For example, the values may have an acceptabledeviation of e.g., about 20%, 15%, 10%, 5%, 3%, 2% or 1%. In aparticular embodiment, the 2-theta values (°) or the d-spacing values(A) of the XRPD pattern of the crystalline forms of the currentinvention may have an acceptable deviation of ±0.2 degrees and/or +0.2Å. Further, the XRPD pattern of the Crystalline Forms of the inventionmay be identified by the characteristic peaks as recognized by oneskilled in the art. For example, the Crystalline Forms of the inventionmay be identified by, e.g., two characteristic peaks, in some instances,three characteristic peaks, in another instance, five characteristicpeaks. Therefore, the term “substantially as” set forth in a particulartable or depicted or shown in a particular figure refers to any crystalwhich has an XRPD having the major or characteristic peaks as set forthin the tables/figures as recognized by one skilled in the art.

It is also to be understood that the differential scanning calorimetryor thermogravimetric analysis thermograms of a given sample may vary(standard deviation) depending on the instrument used, the time andtemperature of the sample when measured, and standard experimentalerrors. The temperature value itself may deviate by +10° C., preferably+5° C., preferably +3° C. of the reference temperature.

Under most circumstances for XRPDs, peaks within the range of up toabout 30° 20 are selected. Rounding algorithms are used to round eachpeak to the nearest 0.1° or 0.01° 2θ, depending upon the instrument usedto collect the data and/or the inherent peak resolution. Peak positionvariabilities are given to within +0.2° 2θ.

The wavelength used to calculate d-spacings (A) values herein is1.5405929 Å, the Cu—K_(α1) wavelength (Phys. Rev., A56 (6), 4554-4568(1997)).

Per USP guidelines, variable hydrates and solvates may display peakvariances greater than +0.2° 20.

“Prominent peaks” are a subset of the entire observed peak list and areselected from observed peaks by identifying preferably non-overlapping,low-angle peaks, with strong intensity.

If multiple diffraction patterns are available, then assessments ofparticle statistics (PS) and/or preferred orientation (PO) are possible.Reproducibility among XRPD patterns from multiple samples analyzed on asingle diffractometer indicates that the particle statistics areadequate. Consistency of relative intensity among XRPD patterns frommultiple diffractometers indicates good orientation statistics.Alternatively, the observed XRPD pattern may be compared with acalculated XRPD pattern based upon a single crystal structure, ifavailable. Two-dimensional scattering patterns using area detectors canalso be used to evaluate PS/PO. If the effects of both PS and PO aredetermined to be negligible, then the XRPD pattern is representative ofthe powder average intensity for the sample and prominent peaks may beidentified as “representative peaks.” In general, the more datacollected to determine representative peaks, the more confident one canbe of the classification of those peaks.

“Characteristic peaks,” to the extent they exist, are a subset ofrepresentative peaks and are used to differentiate one crystallinepolymorph from another crystalline polymorph (polymorphs beingcrystalline forms having the same chemical composition). Characteristicpeaks are determined by evaluating which representative peaks, if any,are present in one crystalline polymorph of a compound against all otherknown crystalline polymorphs of that compound to within +0.2° 2θ. Notall crystalline polymorphs of a compound necessarily have at least onecharacteristic peak.

It has been observed that in reactions to make Crystalline Form A,Crystalline Form B may also form. However, synthesis of products may becontrolled by, for example, seeding with Crystalline Form A.

The Crystalline Form A through F, e.g., formulae 1.1-1.239, e.g.,formulae 2.1-2.30, and combinations thereof as described herein areuseful as an unbalanced triple reuptake inhibitor (TRI), most potenttowards norepinephrine reuptake (NE), one-sixth as potent towardsdopamine reuptake (DA) and one-fourteenth as much towards serotoninreuptake (5-HT). Therefore, the Crystalline Form A through F, e.g.,formulae 1.1-1.239, e.g., formulae 2.1-2.30, and combinations thereof asdescribed herein are useful for the prophylaxis or treatment of adisorder and/or alleviation of associated symptoms of any disordertreatable by inhibiting reuptake of multiple biogenic amines causallylinked to the targeted CNS disorder, wherein the biogenic aminestargeted for reuptake inhibition are selected from norepinephrine,and/or serotonin, and/or dopamine. Therefore, the invention provides amethod for the prophylaxis or treatment of any of the followingdisorders:

-   -   attention deficit hyperactivity disorder (ADHD) and related        behavioral disorders, as well as forms and symptoms of substance        abuse (alcohol abuse, drug abuse), obsessive compulsive        behaviors, learning disorders, reading problems, gambling        addiction, manic symptoms, phobias, panic attacks, oppositional        defiant behavior, conduct disorder, academic problems in school,        smoking, abnormal sexual behaviors, schizoid behaviors,        somatization, depression, sleep disorders, generalized anxiety,        stuttering, and tic disorders. Further disorders are disclosed        in U.S. Publication No. 2007/0082940, the contents of which are        hereby incorporated by reference in their entirety;    -   depression, anxiety disorders, autism, traumatic brain injury,        cognitive impairment, and schizophrenia (particularly for        cognition), obesity, chronic pain disorders, personality        disorder, and mild cognitive impairment;    -   panic disorder, posttraumatic stress disorder, obsessive        compulsive disorder, schizophrenia and allied disorders,        obesity, tic disorders, Parkinson's disease;    -   disorders disclosed in WO 2013/019271, the contents of which are        hereby incorporated by reference in their entirety;    -   fragile X-associated disorder;    -   fragile X-associated disorder wherein the patient was refractory        to a prior course of treatment for the fragile X-associated        disorder;    -   attention-deficit/hyperactivity disorder (ADHD) wherein the ADHD        is co-morbid with one or both of anxiety and depression (e.g.,        depression), e.g., in a patient with a fragile X-associated        disorder;    -   autism spectrum disorder (ASD);    -   disorders disclosed in International Application No.        PCT/US2014/069401, the contents of which are hereby incorporated        by reference in their entirety,        comprising administering to a patient in need thereof a        therapeutically effective amount of any of Crystalline Form A        through F according to any of formulae 1.1-1.239, e.g.,        Crystalline Form A, e.g., any of formulae 1.1-1.77, e.g.,        Crystalline Form B, e.g., any of formulae 1.78-1.162, e.g., any        of formulae 2.1-2.30.

Disorders contemplated for treatment employing the Crystalline Forms ofthe invention as described herein include disorders in the QuickReference to the Diagnostic Criteria From DSM-IV (Diagnostic andStatistical Manual of Mental Disorders, Fourth Edition), The AmericanPsychiatric Association, Washington, D.C., 1994. These target disorders,include, but are not limited to, Attention-Deficit/HyperactivityDisorder, Predominately Inattentive Type;Attention-Deficit/Hyperactivity Disorder, PredominatelyHyperactivity-Impulsive Type; Attention-Deficit/Hyperactivity Disorder,Combined Type; Attention-Deficit/Hyperactivity Disorder not otherwisespecified (NOS); Conduct Disorder; Oppositional Defiant Disorder; andDisruptive Behavior Disorder not otherwise specified (NOS).

Depressive disorders amenable for treatment and/or prevention accordingto the invention include, but are not limited to, Major DepressiveDisorder, Recurrent; Dysthymic Disorder; Depressive Disorder nototherwise specified (NOS); and Major Depressive Disorder, SingleEpisode.

Addictive disorders amenable for treatment and/or prevention employingthe methods and compositions of the invention include, but are notlimited to, eating disorders, impulse control disorders, alcohol-relateddisorders, nicotine-related disorders, amphetamine-related disorders,cannabis-related disorders, cocaine-related disorders, hallucinogen usedisorders, inhalant-related disorders, and opioid-related disorders.

Preferably, the Crystalline Form of the invention is Crystalline Form A.

As used herein, “therapeutically effective amount” refers to an amounteffective, when administered to a human or non-human patient, to providea therapeutic benefit such as amelioration of symptoms. The specificdose of substance administered to obtain a therapeutic benefit will, ofcourse, be determined by the particular circumstances surrounding thecase, including, for example, the specific substance administered, theroute of administration, the condition being treated, and the individualbeing treated.

A dose or method of administration of the dose of the present disclosureis not particularly limited. Dosages employed in practicing the presentdisclosure will of course vary depending, e.g. on the mode ofadministration and the therapy desired. In general, satisfactoryresults, are indicated to be obtained on oral administration at dosagesof the order from about 0.01 to 2.0 mg/kg. An indicated daily dosage fororal administration may be in the range of from about 0.75 mg to 200 mg,conveniently administered once, or in divided doses 2 to 4 times, dailyor in sustained release form. Unit dosage forms for oral administrationthus for example may comprise from about 0.2 mg to 75 mg or 150 mg, e.g.from about 0.2 mg or 2.0 mg or 50 mg or 75 mg or 100 mg to 200 mg or 500mg of any of Crystalline Forms A through F or combinations thereof,preferably Crystalline Form A, e.g., any of formulae 1.1-1.77, togetherwith a pharmaceutically acceptable diluent or carrier therefor.

The Crystalline Forms of the invention may be administered by anysuitable route, including orally, parenterally, transdermally, or byinhalation, including by sustained release, although various other knowndelivery routes, devices and methods can likewise be employed. In someembodiments, provided is a sustained release pharmaceutical composition,e.g., an oral sustained release pharmaceutical composition, comprisingany of the Crystalline Forms of the invention, e.g., Crystalline Form A,e.g., any of formulae 1.1-1.77, over a sustained delivery period ofapproximately 6 hours or longer, e.g., 8 hours or longer, e.g., 12 hoursor longer, e.g., 18 hours or longer, e.g., 24 hours or longer. In someembodiments, provided is an immediate release pharmaceuticalcomposition, e.g., an oral immediate release pharmaceutical composition,comprising any of the Crystalline Forms of the invention, e.g.,Crystalline Form A, e.g., any of formulae 1.1-1.77.

Further dosage and formulation are provided in International ApplicationNo. PCT/US2014/069401 and International Application No.PCT/US2014/069416, the contents of each of which are hereby incorporatedby reference in their entirety.

(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in hydrochloricacid addition salt form may be prepared as described in U.S. PatentPublication No. 2007/0082940 or International Publication No. WO2013/019271, both of which are incorporated herein by reference in theirentirety.

While both U.S. Patent Publication No. 2007/0082940 and InternationalPublication No. WO 2013/019271 describe synthesis of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride,neither discuss any particular crystal form of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride.

The following section illustrates methods of making and characterizingCrystalline Forms A through F of the invention. Both thermodynamic andkinetic crystallization techniques are employed. These techniques aredescribed in more detail below.

Antisolvent Precipitation: Solutions are prepared in various solventsand filtered through a 0.2-μm nylon filter into a vial. Antisolvent isthen added until precipitation is observed. The resulting solids areisolated by vacuum filtration and analyzed.

Crash Cool (CC): Solutions are prepared in various solvents at anelevated temperature and filtered warm through a 0.2-μm nylon filterinto a pre-cooled vial. The vial is placed in a (dry ice+isopropanol)cooling bath. Samples are placed into a freezer if no solids areobserved to immediately precipitate. The resulting solids are isolatedby vacuum filtration and analyzed.

Fast Evaporation (FE): Solutions are prepared in various solvents andsonicated between aliquot additions to assist in dissolution. Once amixture reaches complete dissolution, as judged by visual observation,the solution is filtered through a 0.2-μm nylon filter. The filteredsolution is allowed to evaporate at ambient conditions in an uncappedvial. Solutions are evaporated to dryness unless designated as partialevaporations. The solids that formed are isolated and analyzed.

Freeze-Drying (Lyophilization): Solutions are prepared in 1:1 dioxane:water or water, filtered through a 0.2-μm nylon filter, and frozen in avial or flask immersed in a bath of dry ice and isopropanol. The vial orflask containing the frozen sample is attached to a Flexi-Drylyophilizer and dried for a measured time period. After drying, thesolids are isolated and stored in the freezer over desiccant until use.

Milling: A solid sample is placed into a stainless steel grinding jarwith a grinding ball. The sample is then ground at 30 Hz on a ball mill(Retsch Mixer Mill model MM200) for a set amount of time. The solids arecollected and analyzed.

Relative Humidity Stress: Solids are stored at approximately 40° C./75%RH condition for a measured time period by placing the solids into avial inside a sealed temperature/humidity chamber at the controlledcondition. Samples are analyzed after removal from the stressenvironment.

Rotary Evaporation: Solutions of the Compound in hydrochloric acidaddition salt form((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) inHFIPA are prepared. Solids are obtained by rotary evaporation of thesolvent under vacuum, with the sample vial immersed in a heated waterbath at approximately 40° C. Solids are then dried for an additionalapproximate 10 minutes under vacuum at ambient temperature. Afterevaporation, the solids are stored in the freezer over desiccant untiluse.

Slow Cooling (SC): Solutions are prepared in various solvents at anelevated temperature. The solutions are filtered warm through a 0.2-μmnylon filter into a warm vial. The vial is capped and left on the hotplate, and the hot plate is turned off to allow the sample to coolslowly to ambient temperature. If no solids are present after cooling toambient temperature, the sample is placed in a refrigerator and/orfreezer for further cooling. Solids are collected by vacuum filtrationand analyzed.

Slow Evaporation (SE): Solutions are prepared in various solvents andsonicated to assist in dissolution. Once a mixture reaches completedissolution, as judged by visual observation, the solution is filteredthrough a 0.2-μm nylon filter. The filtered solution is allowed toevaporate at ambient conditions in a vial covered with aluminum foilperforated with pinholes. Solutions are evaporated to dryness unlessdesignated as partial evaporations. The solids that form are isolatedand analyzed.

Slurry Experiments: Suspensions are prepared by adding enough solids toa given solvent so that excess solids are present. The mixture is thenagitated in a sealed vial at ambient temperature or an elevatedtemperature. After a given period of time, the solids are isolated byvacuum filtration and analyzed.

Vapor Diffusion (VD): Solutions are prepared in various solvents andfiltered through a 00.2-μm nylon filter. The filtered solution isdispensed into a 1-dram vial, which is then placed inside a 20-mL vialcontaining antisolvent. The 1-dram vial is left uncapped and the 20-mLvial is capped to allow vapor diffusion to occur. The resulting solidsare isolated and analyzed.

Vapor Stress (VS): A solid sample is placed into a 1-dram vial. The1-dram vial is then placed into a 20-mL vial containing solvent. The20-mL vial is capped and left at ambient conditions for a measured timeperiod. Samples are analyzed after removal from the stress environment.

XRPD Overlays: The overlays of XRPD patterns are generated using PatternMatch 2.3.6.

XRPD Indexing: The high-resolution XRPD patterns of Crystalline Forms ofthe invention are indexed using X'Pert High Score Plus (X'Pert HighScore Plus 2.2a (2.2.1)) or proprietary software. Indexing and structurerefinement are computational studies.

Instrumental Techniques: The test materials in this study are analyzedusing the instrumental techniques described below.

Differential Scanning Calorimetry (DSC): DSC is performed using a TAInstruments differential scanning calorimeter. Temperature calibrationis performed using NIST traceable indium metal. The sample is placedinto an aluminum DSC pan, covered with a lid, and the weight isaccurately recorded. A weighed aluminum pan configured as the sample panis placed on the reference side of the cell. The data acquisitionparameters and pan configuration are displayed in the image of eachthermogram. The method code on the thermogram is an abbreviation for thestart and end temperature as well as the heating rate; e.g., −30-250-10means “from −30° C. to 250° C., at 10° C./min”. The following tablesummarizes the abbreviations used in each image for pan configurations:

Abbreviation Meaning T0C Tzero crimped pan HS Lid hermetically sealedHSLP Lid hermetically sealed and perforated with a laser pinhole C Lidcrimped NC Lid not crimped

Thermogravimetric Analysis (TGA): TG analyses are performed using a TAInstruments thermogravimetric analyzer. Temperature calibration isperformed using nickel and Alumel™. Each sample is placed in an aluminumpan. The sample is hermetically sealed, the lid pierced, then insertedinto the TG furnace. The furnace is heated under nitrogen. The dataacquisition parameters are displayed in the image of each thermogram.The method code on the thermogram is an abbreviation for the start andend temperature as well as the heating rate; e.g., 25-350-10 means “from25° C. to 350° C., at 10° C./min”.

X-ray Powder Diffraction (XRPD): Inel XRG-300. X-ray powder diffractionanalyses are performed on an Inel XRG-3000 diffractometer, equipped witha curved position-sensitive detector with a 2θ range of 120°. Real timedata is collected using Cu Kα radiation at a resolution of 0.03 °2θ. Thetube voltage and amperage are set to 40 kV and 30 mA, respectively.Patterns are displayed from 2.5 to 40 °2θ to facilitate direct patterncomparisons. Samples are prepared for analysis by packing them intothin-walled glass capillaries. Each capillary is mounted onto agoniometer head that is motorized to permit spinning of the capillaryduring data acquisition. Instrument calibration is performed daily usinga silicon reference standard. The data acquisition and processingparameters are displayed on each pattern found in the data section.

X-ray Powder Diffraction (XRPD): Bruker D-8 Discover Diffractometer.XRPD patterns are collected with a Bruker D-8 Discover diffractometerand Bruker's General Area Diffraction Detection System (GADDS, v.4.1.20). An incident beam of Cu Kα radiation is produced using afine-focus tube (40 kV, 40 mA), a Gobel mirror, and a 0.5 mmdouble-pinhole collimator. The sample is packed between 3-micron thickfilms to form a portable disc-shaped specimen. The prepared specimen isloaded in a holder secured to a translation stage and analyzed intransmission geometry. The incident beam is scanned and rastered tooptimize orientation statistics. A beam-stop is used to minimize airscatter from the incident beam at low angles. Diffraction patterns arecollected using a Hi-Star area detector located 15 cm from the sampleand processed using GADDS. Prior to the analysis a silicon standard isanalyzed to verify the Si 111 peak position. The data acquisition andprocessing parameters are displayed on each pattern found in the datasection.

X-ray Powder Diffraction (XRPD): PANalytical X'Pert Pro Diffractometer.XRPD patterns are collected using a PANalytical X'Pert Prodiffractometer. The specimen is analyzed using Cu radiation producedusing an Optix long fine-focus source. An elliptically graded multilayermirror is used to focus the Cu Kα X-rays of the source through thespecimen and onto the detector. The specimen is sandwiched between3-micron thick films, analyzed in transmission geometry, and rotatedparallel to the diffraction vector to optimize orientation statistics. Abeam-stop, short antiscatter extension, antiscatter knife edge, andhelium purge are used to minimize the background generated by airscattering. Soller slits are used for the incident and diffracted beamsto minimize axial divergence. Diffraction patterns are collected using ascanning position-sensitive detector (X'Celerator) located 240 mm fromthe specimen. The data-acquisition parameters of each diffractionpattern are displayed above the image of each pattern in the datasection. Prior to the analysis, a silicon specimen (NIST standardreference material 640d) is analyzed to verify the position of thesilicon 111 peak.

For indexing, agreement between the allowed peak positions, marked withbars, and the observed peaks indicates a consistent unit celldetermination. Successful indexing of the pattern indicates that thesample is composed primarily of a single crystalline phase. Space groupsconsistent with the assigned extinction symbol, unit cell parameters,and derived quantities are tabulated below the figure. To confirm thetentative indexing solution, the molecular packing motifs within thecrystallographic unit cells must be determined. No attempts at molecularpacking are performed.

Abbreviations

-   acetonitrile (ACN)-   birefringence (B)-   brine (saturated aqueous solution of sodium chloride)-   density (d)-   dichloromethane (DCM)-   equivalents (eq)-   ethanol (EtOH)-   ethyl acetate (EtOAc)-   extinction (E)-   formula weight (FW)-   gram (g)-   hour or hours (h, hrs)-   hexafluoroisopropanol (HFIPA)-   high performance (pressure) liquid chromatography (HPLC)-   isopropanol (IPA)-   isopropyl acetate (IPAc)-   isopropyl ether (IPE)-   kilogram (kg)-   liters (L)-   methanol (MeOH)-   methyl ethyl ketone (MEK)-   minute(s) (min)-   millilitres (mL)-   molarity of a solution (mol/L) (M)-   molecular weight (MW)-   moles (mol)-   room temperature (RT)-   saturated (sat)-   sodium hexamethyldisilylazane (NaHMDS)-   starting material (SM)-   tetrahydrofuran (THF)-   2,2,2,-trifluoroethanol (TFE)-   versus (vs)-   weight (wt)

Example 1—Preparation of Crystalline Form A

MW d Compound (g/mol) (g/mL) Equivalents Amt/mol Reaction2-naphthylacetonitrile 167.21 NA 1.0 mol eq (SM) 1500 g/8.97 mol(S)-(+)-epichlorohydrin  92.52 3.12 1.30 mol eq  1081 g/11.67 moltetrahydrofuran  72.11 0.889 6.0 ml/g SM 9.0 L 2M sodiumbis(trimethylsilyl)amide   2.0M 0.916 2 mol eq   9.0 L/18.6 mol in THF2M sodium bis(trimethylsilyl)amide   2.0M 0.916 0.067 mol eq  0.30L/0.60 mol in THF borane-dimethylsulfide   10.0M 0.80 2.5 mol eq 2.25 L borane-dimethylsulfide   10.0M 0.80 0.39 mol eq 0.35 L  Isolation 2M HCl(aqueous)   2M NA 11.5 mL/g SM 17.3 L  isopropyl acetate 102.13 0.872 4mL/g SM 6.0 L water  18.02 1.00 5 mL/g SM 7.5 L ammonia (aqueous) NA0.889 1.5 mL/g SM 2.25 L  isopropyl acetate 102.13 0.872 5 mL/g SM 7.5 Lisopropyl acetate 102.13 0.872 5 mL/g SM 7.5 L 5% aqueous dibasic sodiumNA NA 4 mL/g SM 6.0 L phosphate brine saturated NA NA 4 mL/g SM 6.0 Lisopropyl acetate 102.13 0.872 10 mL/g SM  15 L para-toluenesulfonicacid- 190.22 NA 0.93 mol eq 1586 g/8.34 mol monohydrate isopropylacetate 102.13 0.872 2 mL/g SM 3.0 L isopropyl acetate 102.13 0.872 2mL/g SM 3.0 L

Charge 2-naphthylacetonitrile (1500 g, 8.97 mol, SM) to a 3-neck, 50 Lround bottom flask equipped with an overhead stirrer, addition funnel,thermocouple, cooling bath, nitrogen inlet and drying tube. Chargetetrahydrofuran (6.0 L, 4 mL/g, SM) to the reaction vessel. Stir at roomtemperature until all of the 2-naphthylacetonitrile is dissolved. Charge(S)-(+)-epichlorohydrin (1081 g, 11.67 mol, 1.30 eq) to the reactionvessel. Cool the reaction mixture to an internal temperature of −28° C.Use dry ice/acetone bath to cool. Dry ice added to bath intermittentlyto keep cooling bath between −35 and −25° C. during sodiumbis(trimethylsilyl)amide addition. Charge a solution of sodiumbis(trimethylsilyl)amide in THF (9.0 L, 18.0 mol, 2 mol eq) to theaddition funnel and slowly add to the chilled reaction mixture at a ratesuch that the internal temperature remains at less than −14° C. Additionrequires 1 hr 40 minutes. During the addition the internal temperatureis generally between −20 and −17° C. After completion of the addition,the resulting solution is stirred at between −21 and −16° C. for 2 hours30 minutes. Monitor the reaction by HPLC. Maintain −20 to −15 OCtemperature of the reaction mixture while analyzing sample by HPLC.

HPLC assay at 2 hr 30 minutes shows reaction is not complete. Addadditional sodium bis(trimethylsilyl)amide in THF (0.30 L, 0.60 mol,0.067 mole eq) over 10 minutes via addition funnel, keeping the internaltemperature of the reaction mixture less than −15° C. Stir 15 minutes atwhich point HPLC assay shows reaction is complete. Chargeborane-dimethylsulfide (2.25 L, 22.5 mol, 2.5 mole eq) complex viaaddition funnel at a rate such that the internal temperature of thereaction mixture remains below 0° C. Addition requires 40 minutes. Aftercompletion of the borane addition slowly heat the reaction mixture to40° C. Once an internal temperature of 40° C. is obtained discontinueheating. A slow steady exotherm over approximately two hours is observedwhich results in a maximum internal temperature of 49° C. Uponcompletion of the exotherm increase the internal temperature to 60° C.Stir reaction mixture overnight at 60° C. Monitor the reaction by HPLC.Maintain 60° C. temperature of the reaction mixture while analyzingsample by HPLC.

Charge additional borane-dimethylsulfide (0.35 L, 0.70 mol, 0.39 moleeq) to reaction mixture via addition funnel. Stir the reaction mixture 3hours 30 minutes at 60° C. Cool reaction mixture to room temperature.

To a second 3-neck, 50 L round bottom flask equipped with an overheadstirrer, thermocouple, cooling bath, and nitrogen inlet charge 2M HCl inwater (17.3 L, 11.5 mL/g SM, prepared from 2.9 L concentrated HCl and14.4 L water). Cool HCl/water solution to 3° C. Slowly transfer roomtemperature reaction mixture containing the cyclopropyl amine to thechilled HCl solution at a rate such that the maximum internaltemperature of the quench mixture is 23° C. Quench requires 2 hr 50minutes. When the reaction quench is complete, heat the two phasemixture to 50° C. Stir for one hour at 50° C. Cool to room temperature.Add isopropylacetate (6.0 L, 4 mL/g SM). Add water (7.5 L, 5 mL/g SM).Agitate mixture for a minimum of 15 minutes. Discontinue agitation andallow layers to settle for a minimum of 30 minutes. Discard the organic(upper) layer. Add aqueous ammonia (2.25 L, 1.5 mL/g SM) to the aqueouslayer. Add isopropylacetate (7.5 L, 5 mL/g). Agitate mixture for aminimum of 15 minutes. Discontinue agitation and allow layers to settlefor a minimum of 30 minutes. Separate layers. Product is in the organic(upper) layer. Add isopropylacetate (7.5 L, 5 mL/g SM) to aqueous layer.Agitate mixture for a minimum of 15 minutes. Discontinue agitation andallow layers to settle for a minimum of 30 minutes. Separate layers.Product is in the organic (upper) layer. Combine the twoisopropylacetate extracts. Add 5% dibasic sodium phosphate in water (6.0L, 4 mL/g SM) to combined extracts. Agitate mixture for a minimum of 15minutes. Discontinue agitation and allow layers to settle for a minimumof 30 minutes. Separate layers and discard aqueous (lower) layer. Addsaturated brine (6.0 L, 4 mL/g SM) to combined extracts. Agitate mixturefor a minimum of 15 minutes. Discontinue agitation and allow layers tosettle for a minimum of 30 minutes. Separate layers and discard aqueous(lower) layer. Concentrate the final organic layer in a tared 20 L Buchiflask in vacuo. Obtain a total of 1967.6 g of a light orange waxy solid.Transfer solids to a 50 L 3-neck round bottom flask equipped with anoverhead stirrer, thermocouple, heating mantel, nitrogen inlet anddrying tube. Add isopropyl acetate (15 L, 10 mL/g SM). Heat the mixtureto 50° C. Add p-toluene sulfonic acid monohydrate (1586 g, 8.34 mol,0.93 mole eq) in portions over 30 minutes keeping the temperature lessthan 60° C. Upon completion of the addition discontinue heating andallow the mixture to cool to room temperature. Collect the solids byfiltration. Wash the filtercake with isopropyl acetate (3 L, 2 mL/g SM).Wash the filtercake a second time with isopropyl acetate (3 L, 2 mL/gSM). Dry filtercake to a constant weight in the filter funnel by pullingair through the cake using vacuum. After an initial drying period thefiltercake is broken up with a spatula and the cake agitated atintervals to promote drying. Obtain 2049 g of a white solid. HPLC assay:98.2% for the main peak and a cis:trans ratio of 98.5:1.5.

MW d Compound (g/mol) (g/mL) Equivalents Amt/mol Reactionnaphthylcyclopropylamine-tosylate 399.51 NA  1.0 mole eq  2037.9 g/5.10mol salt isopropylacetate 102.13 0.872  6.5 mL/g SM 13.2 L  thionylchloride 118.97 1.638  1.2 eq 445 mL/6.13 mol 5M NaOH 5.0M NA  6.0 moleq  6.1 L/30.5 mol Isolation 1M NaOH 1.0M NA   1 mL/g SM 2.1 L isopropylacetate (back extraction) 102.13 0.872 3.75 mL/g SM 7.6 L saturatedbrine NA NA   2 mL/g SM 4.1 L magnesium sulfate NA NA NA NAisopropylacetate (wash) 102.13 0.872  0.5 mL/g SM 1.0 L isopropylacetate(dilution) 102.13 0.872  3.5 mL/g SM 7.2 L hydrogen chloride inisopropyl 5.7M NA  1.0 eq 0.90 L  alcohol isopropylacetate (wash) 102.130.872 1.13 mL/g SM 2.3 L isopropylacetate (wash) 102.13 0.872 1.13 mL/gSM 2.3 L isopropyl alcohol 60.1 0.786 7.45 mL/g SM 34.6 L  isopropylalcohol 60.1 0.786  1.5 mL/g SM 6.9 L isopropyl alcohol 60.1 0.786  1.5mL/g SM 6.9 L

Note: Addition of 5 M NaOH to the reaction mixture is exothermic andrequires active cooling.

Charge 2039.7 g (5.10 mol, 1.0 mol eq) of thenaphthylcyclopropylamine-tosylate salt obtained above to a 50 L 3-neckround bottom flask equipped with an overhead stirrer, thermocouple,addition funnel, nitrogen inlet, drying tube and room temperature waterbath. Charge 13.2 L of isopropyl acetate (IPAc, 13.2 L, 6.5 mL/g SM) tothe reaction flask and stir at room temperature to give an white slurry.Add 445 mL of thionyl chloride (6.13 mol, 1.2 mol eq) via the additionfunnel keeping the temperature less than 25° C. Addition requires 1 hr 5minutes. Stir the thick slurry at ambient temperature for a minimum oftwo hours. Monitor the reaction by HPLC. Maintain the reaction mixtureat ambient temperature while analyzing sample by HPLC. Add 5M NaOH (6.1L, 30.5 mol, 6.0 mol eq) via addition funnel using an ice/water bath tokeep less than 30° C. Addition requires 1 hr 40 min. Monitor thereaction by HPLC. Maintain the reaction mixture at ambient temperaturewhile analyzing sample by HPLC. Stir reaction mixture at 25° C. for 1 hr5 min then allow layers to settle. Separate the layers. Wash the organic(upper) layer with 1M NaOH (2.1 L, 1 mL/g SM). Combine the two aqueouslayers. Back extract the combined aqueous layers with isopropylacetate(7.6 L, 3.75 mL/g SM). Combine the washed organic layer and the backextract. Wash the combined organic layers with saturated brine (4.1 L, 2mL/g SM). Dry organic layers over granular magnesium sulfate. Filter toremove solids. Wash filtercake with isopropylacetate (1 L, 0.5 mL/g SM).Concentrate combined filtrate and wash in a 20 L Buchi Rotavap flask toa total volume of 4.2 L. Transfer to a 22 L 3-neck round bottom flaskequipped with overhead stirrer, addition funnel, thermocouple, coolingbath, nitrogen inlet, and drying tube. Dilute with isopropylacetate (7.2L, total volume of solution=11.4 L, 5.6 mL/g SM). Add hydrogen chloridein isopropyl alcohol (5.7 M, 0.90 L, 5.13 mol, 1.0 mol eq) via additionfunnel over 50 minutes at a rate such that the internal temperatureremains below 30° C. Stir the slurry for 45 minutes at room temperature.Filter to collect solids. Wash filtercake with isopropylacetate (2.3 L,1.13 mL/g SM). Wash filtercake a second time with isopropylacetate (2.3L, 1.13 mL/g SM). Partially dry filtercake by pulling air through thecake with vacuum. HPLC assay of the wet cake shows 96.3 area percentpurity and an EE of 89.5%.

Combine wet cakes from this experiment and from another batch in a 50 L3-neck round bottom flask equipped with overhead stirrer, heatingmantel, thermocouple, reflux condenser, nitrogen inlet, and drying tube.Add isopropyl alcohol (34.6 L, 7.45 mL/g SM). Heat the slurry to reflux.Maintain reflux for three hours. Discontinue heating and allow to coolto room temperature. Filter to collect solids. Wash filtercake withisopropyl alcohol (6.9 L, 1.5 mL/g SM). Wash filtercake a second timewith isopropyl alcohol (6.9 L, 1.5 mL/g SM). Dry filtercake to aconstant weight by pulling air through the cake using vacuum. Obtain2009 g of product as a tan solid. HPLC: >99.5%. Chiral HPLC: 95.4%.

MW d Compound (g/mol) (g/mL) Equivalents Amt/mol Reaction(1R,5S)-1-(naphthalen-2- 245.74 NA 1.0 2009 g yl)-3-azabicyclo[3.1.0]-hexane hydrochloride ethanol (special industrial) 46.07 0.789 10.7 mL/g21.5 L Isolation ethanol (SI), wash 46.07 0.789 2.14 mL/g 4.3 L

Note: Minimal amount of ethanol necessary to completely dissolve thestarting material should be used.

Charge (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexanehydrochloride to a 50 L 3-neck round bottom flask equipped with anoverhead stirrer, thermocouple, reflux condenser, heating mantel,nitrogen inlet and drying tube. Add ethanol (20 L, mL/g SM). Heat thestirred slurry to 77° C. Add additional ethanol in 0.5 L aliquots andreturn mixture to reflux until all solids dissolve. Complete dissolutionafter the addition of 1.5 L additional ethanol, 21.5 L total.Discontinue heating and allow solution to cool to room temperature.Filter to collect solids. Wash filtercake with ethanol (4.3 L, 2.14 mL/gSM). Dry filtercake to a constant weight by pulling air through thefiltercake using vacuum. Obtain 1435 g of light tan solids. Yield=74%.HPLC: 99.5%. Chiral HPLC: 99.9%.

MW d Compound (g/mol) (g/mL) Equivalents Amt/mol Reaction(1R,5S)-1-(naphthalen-2-yl)-3- 245.74 NA  1.0 mol eq 1406 g/5.72 molazabicyclo[3.1.0]hexane hydrochloride (SM) water 18.02 1.0    10 mL/g SM14.0 tetrahydrofuran 72.11 0.889   2 mL/g SM 2.8 L isopropylacetate102.13 0.872   2 mL/g SM 2.8 L Isolation ammonia (aqueous) 15.0M 0.90  3.0 mol eq  1.14 L/17.1 mol isopropyl acetate 102.13 0.872   10 mL/g SM14.0 L  magnesium sulfate NA NA NA NA isopropyl acetate (wash) 102.130.872 1.42 mL/g SM 2.0 L isopropyl alcohol 60.1 0.786   10 mL/g SM 14.0L  hydrogen chloride in isopropyl alcohol 5.7M NA 0.84 mol eq  845 mLhydrogen chloride in isopropyl alcohol 5.6M NA 0.11 mol eq  110 mLhydrogen chloride in isopropyl alcohol 5.6M NA 0.06 mol eq   60 mLisopropyl alcohol (wash one) 60.1 0.786  2.0 mL/g SM 2.8 L isopropylalcohol (wash two) 60.1 0.786  2.0 mL/g SM 2.8 L

Charge the Compound in hydrochloric acid addition salt form((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride)(1406 g, 5.72 mol, 1.0 mol eq) (the compound obtained from the stepabove and another batch) to a 22 L, 3-neck round bottom flask equippedwith an overhead stirrer, heating mantel, thermocouple, and nitrogeninlet. Add water (14 L, 10 mL/g SM). Heat the slurry to an internaltemperature of 34° C. to dissolve all solids. Transfer to a largeseparatory funnel. Add tetrahydrofuran (2.8 L, 2 mL/g SM). Addisopropylacetate (2.8 L, 2 mL/g SM). Discontinue stirring and allowlayers to separate. Discard the organic (upper) layer. Product is in thelower (aqueous) layer. To the aqueous (lower) layer add aqueous ammonia(1.14 L, 17.1 mol, 3.0 mol eq). Add isopropylacetate (14.0 L, 10 mL/gSM). Agitate mixture for a minimum of 15 minutes. Discontinue agitationand allow layers to settle for a minimum of 30 minutes. Separate thelayers. Product is in the organic (upper) layer. Add granular magnesiumsulfate to the organic layer. Filter to remove solids. Wash thefiltercake with isopropylacetate (1 L). Wash the filtercake a secondtime with isopropylacetate (1 L). Concentrate combined filtrate andwashes in a 20 L Buchi rotavap flask to give an off-white solid. Chargesolid to a 22 L round bottom flask equipped with overhead stirrer,thermocouple, addition funnel, nitrogen inlet and drying tube. Addisopropyl alcohol (14 L, 10 mL/g SM). Stir at room temperature todissolve all solids. Charge 5.7 N HCl in IPA (175 mL, 1.0 mol, 0.17 moleq) via addition funnel over 10 minutes to form white solids. Stir thethin slurry at room temperature for 30 minutes. Charge 5.7 N HCl in IPA(670 mL, 3.82 mol, 0.67 mol eq) followed by 5.6 N HCl in IPA (110 mL,0.62 mol, 0.11 mol eq) via addition funnel over 55 minutes. Stir theslurry for 35 minutes then assay the mother liquors for loss. Add 5.6 NHCl in IPA (60 mL, 0.34 mol, 0.06 mol eq) over 10 minutes via additionfunnel. Stir the slurry for 30 minutes then assay the mother liquors forloss. Filter to collect solids. Wash filtercake with isopropyl alcohol(2.8 L, 2 mL/g SM). Wash filtercake a second time with isopropyl alcohol(2.8 L, 2 mL/g SM). Dry filtercake to a constant weight by pulling airthrough the filtercake using vacuum. Obtain 1277 g of product as anoff-white solid. HPLC: 99.9%.

The resulting compound exhibits a crystalline XRPD pattern (FIG. 1), andis designated as Crystalline Form A. The XRPD pattern is collected witha PANalytical X'Pert PRO MPD diffractometer using an incident beam of Curadiation produced using an Optix long, fine-focus source. Anelliptically graded multilayer mirror is used to focus Cu Kα X-raysthrough the specimen and onto the detector. Prior to the analysis, asilicon specimen (NIST SRM 640d) is analyzed to verify the Si 111 peakposition. A specimen of the sample is sandwiched between 3-μm-thickfilms and analyzed in transmission geometry. A beam-stop, shortanti-scatter extension, and an anti-scatter knife edge are used tominimize the background generated by air. Soller slits for the incidentand diffracted beams are used to minimize broadening from axialdivergence. The diffraction pattern is collected using a scanningposition-sensitive detector (X'Celerator) located 240 mm from thespecimen and Data Collector software v. 2.2b. The experimental XRPDpattern is collected according to cGMP specifications. The XRPD patterncollected is shown in FIG. 1 (Panalytical X-Pert Pro MPD PW3040 Pro,X-ray Tube: Cu (1.54059 Å), Voltage: 45 kV, Amperage: 40 mA, Scan Range:1.01-40.00 °2θ, Step Size: 0.017 °2θ, Collection Time: 1939 s, ScanSpeed: 1.2°/min., Slit: DS: ½°, SS: null, Revolution Time: 1.0 s, Mode:Transmission).

Thermal analysis results are shown in FIG. 2 (DSC, Size: 1.7800 mg,Method: (−30)-300-10, TOC; TGA, Size: 6.8320 mg, Method: 00-350-10). ByTGA, Crystalline Form A exhibits approximately 0.4% weight loss up to200° C. The dramatic weight change in the TGA at approximately 276° C.is consistent with decomposition. The DSC thermogram (FIG. 2) displaysmultiple endotherms between approximately 245 and 248° C. concurrentwith the dramatic weight change by TGA, suggesting overlapping eventsare occurring during heating.

Characterization data for Crystalline Form 1 are summarized in Table 1below:

TABLE 1 Analysis Result DSC^(a) 247° C. (endo, peak; 245° C. onset);248° C. (endo, shoulder); 248° C. (endo, peak) TGA^(a) 0.4% weight lossup to 200° C. 276° C. (onset, decomposition) ^(a)Temperatures arerounded to the nearest ° C.; weight loss values are rounded to onedecimal place.

Based on the dynamic vapor sorption/desorption data collected (FIG. 3),Crystalline Form A obtained is a non-hygroscopic material. Upon initialequilibration at 5% RH, Crystalline Form A shows a weight loss of 0.03%;a weight gain of 0.10% is observed from 5% to 95% RH. During thedesorption step from 95% to 5% RH, Crystalline Form A exhibitsapproximately 0.10% weight loss.

Post-Moisture Balance Material is Similar to Starting Material by XRPD(FIG. 50).

Data Acquisition Parameters for Dynamic Vapor Sorption/DesorptionIsotherm:

Notes Range 5% to 95% Drying 25° C. at 10% increments OFF Max Equil Time180 min Equil Crit 0.0100 wt % in 5.00 min T-RH Steps 25, 5; 25, 15; 25,25; 25, 35; 25, 45; 25, 55; 25, 65; 25, 75; 25, 85; 25, 95; 25, 85; 25,75; 25, 65; 25, 55; 25, 45; 25, 35; 25, 25; 25, 15; 25, 5 Data LoggingInterval 2.00 min or 0.0100 wt % Samp Step Time Elap Time Weight WeightTemp Samp RH min min mg % chg deg C. % n/a 0.1 11.532 0.000 25.20 1.7013.1 13.2 11.528 −0.034 25.18 5.06 11.5 24.7 11.529 −0.025 25.19 15.2413.0 37.7 11.529 −0.024 25.22 24.81 13.0 50.7 11.530 −0.019 25.21 34.8217.0 67.7 11.530 −0.016 25.21 44.81 25.0 92.7 11.531 −0.012 25.20 54.8628.3 121.0 11.532 −0.005 25.20 64.82 12.8 133.8 11.533 0.005 25.20 74.6613.0 146.8 11.535 0.024 25.19 84.55 13.3 160.0 11.540 0.068 25.19 94.5410.8 170.8 11.536 0.037 25.18 85.08 11.0 181.8 11.534 0.019 25.18 75.2813.0 194.8 11.532 0.003 25.18 64.96 13.0 207.8 11.531 −0.007 25.18 55.0813.0 220.8 11.531 −0.013 25.18 45.09 13.0 233.8 11.530 −0.016 25.1835.13 13.0 246.8 11.530 −0.021 25.17 25.12 21.0 267.8 11.529 −0.02525.17 15.20 10.0 277.8 11.528 −0.032 25.17 4.95

Example 2—Preparation of Crystals of Form A

Solution of the Compound in hydrochloric acid addition salt form((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride) isprepared using 98.5 mg of the Compound from Example 1 in 2 mL methanoland filtered through a 0.2-μm nylon filter. A 0.5 mL aliquot of thefiltered solution is dispensed into a 1-dram open vial, which is thenplaced inside a 20-mL vial containing 3 mL antisolvent ethyl acetate.The 1-dram vial is left uncapped and the 20-mL vial is capped to allowvapor diffusion to occur. Single crystals are grown in the 1-dram vialafter approximately 7 days.

Data Collection: A colorless plate of C₁₅H₁₆ClN [Cl, C₁₅H₁₆N] havingapproximate dimensions of 0.38×0.30×0.18 mm, is mounted on a fiber inrandom orientation. Preliminary examination and data collection areperformed with Mo Kα radiation (λ=0.71073 Å) on a Nonius Kappa CCDdiffractometer equipped with a graphite crystal, incident beammonochromator. Refinements are performed using SHELX97 (Sheldrick, G. M.Acta Cryst., 2008, A64, 112). Cell constants and an orientation matrixfor data collection are obtained from least-squares refinement using thesetting angles of 5812 reflections in the range 10<θ<27°. The refinedmosaicity from DENZO/SCALEPACK is 0.380 indicating good crystal quality(Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307). The spacegroup is determined by the program XPREP (Bruker, XPREP in SHELXTL v.6.12., Bruker AXS Inc., Madison, Wis., USA, 2002). From the systematicpresence of the following conditions: h00 h=2n; 0k0 k=2n; 00ll=2n, andfrom subsequent least-squares refinement, the space group is determinedto be P2₁2₁2₁ (no. 19). The data are collected to a maximum 20 value of55.710, at a temperature of 150±1 K.

Data Reduction: Frames are integrated with DENZO-SMN (Otwinowski, Z.;Minor, W. Methods Enzymol. 1997, 276, 307). A total of 5812 reflectionsare collected, of which 2930 are unique. Lorentz and polarizationcorrections are applied to the data. The linear absorption coefficientis 0.273 mm⁻¹ for Mo Kα radiation. An empirical absorption correctionusing SCALEPACK (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276,307) is applied. Transmission coefficients range from 0.953 to 0.953.Intensities of equivalent reflections are averaged. The agreement factorfor the averaging is 2.9% based on intensity.

Structure Solution and Refinement: The structure is solved by directmethods using SIR2004 (Burla, M. C., Caliandro, R., Camalli, M.,Carrozzini, B., Cascarano, G. L., De Caro, L., Giacovazzo, C., Polidori,G., and Spagna, R., J. Appl. Cryst. 2005, 38, 381). The remaining atomsare located in succeeding difference Fourier syntheses. Hydrogen atomsare included in the refinement but restrained to ride on the atom towhich they are bonded. The structure is refined in full-matrixleast-squares by minimizing the function:Σw(|F _(o)|² −|F _(c)|²)²The weight w is defined as 1/[σ²(F_(o) ²)+(0.0384P)²+(0.2436P)], whereP=(F_(o) ²+2F_(c) ²)/3. Scattering factors are taken from the“International Tables for Crystallography” (International Tables forCrystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, TheNetherlands, 1992, Tables 4.2.6.8 and 6.1.1.4). Of the 2930 reflectionsused in the refinements, only the reflections with F_(o) ²>2σ(F_(o) ²)are used in calculating R. A total of 2678 reflections are used in thecalculation. The final cycle of refinement includes 162 variableparameters and converges (largest parameter shift is <0.01 times itsestimated standard deviation) with unweighted and weighted agreementfactors of:R=Σ|F _(o) −F _(c) |/ΣF _(o)=0.033R _(w)=(Σw(F _(o) ² −F _(c) ²)² /Σw(F _(o) ²)²)=0.080

The standard deviation of an observation of unit weight (goodness offit) is 1.066. The highest peak in the final difference Fourier has aheight of 0.19 e/Å³. The minimum negative peak has a height of −0.24e/Å³. The Flack factor for the determination of the absolute structure(Flack, H. D. Acta Cryst. 1983, A39, 876) refines to −0.02(6).

Calculated X-Ray Powder Diffraction (XRPD) Pattern: A calculated XRPDpattern is generated for Cu radiation using PowderCell 2.3 (PowderCellfor Windows Version 2.3 Kraus, W.; Nolze, G. Federal Institute forMaterials Research and Testing, Berlin Germany, E U, 1999) and theatomic coordinates, space group, and unit cell parameters from thesingle crystal data. Because the single crystal data are collected atlow temperatures (150 K), peak shifts may be evident between the patterncalculated from low temperature data and the room temperatureexperimental powder diffraction pattern, particularly at highdiffraction angles.

ORTEP and Packing Diagrams: The ORTEP diagram is prepared using theORTEP III (Johnson, C. K. ORTEPIII, Report ORNL-6895, Oak Ridge NationalLaboratory, TN, U.S.A. 1996. OPTEP-3 for Windows V1.05, Farrugia, L. J.,J. Appl. Cryst. 1997, 30, 565) program within the PLATON (Spek, A. L.PLATON. Molecular Graphics Program. Utrecht University, Utrecht, TheNetherlands, 2008. Spek, A. L, J. Appl. Cryst. 2003, 36, 7) softwarepackage. Atoms are represented by 50% probability anisotropic thermalellipsoids. Packing diagrams are prepared using CAMERON (Watkin, D. J.;Prout, C. K.; Pearce, L. J. CAMERON, Chemical CrystallographyLaboratory, University of Oxford, Oxford, 1996) modeling software.Assessment of chiral centers are performed with the PLATON (Spek, A. L.PLATON. Molecular Graphics Program. Utrecht University, Utrecht, TheNetherlands, 2008. Spek, A. L, J. Appl. Cryst. 2003, 36, 7) softwarepackage. Absolute configuration is evaluated using the specification ofmolecular chirality rules (Cahn, R. S.; Ingold, C; Prelog, V. Angew.Chem. Intern. Ed. Eng., 1966, 5, 385; Prelog, V. G. Helmchen Angew.Chem. Intern. Ed. Eng., 1982, 21, 567). Additional figures are generatedwith the Mercury 2.4 (Macrae, C. F. Edgington, P. R. McCabe, P. Pidcock,E. Shields, G. P. Taylor, R. Towler M. and van de Streek, J.; J. Appl.Cryst., 2006, 39, 453-457) visualization package. Hydrogen bonding isrepresented as dashed lines.

Results: The orthorhombic cell parameters and calculated volume are:a=5.7779(2) Å, b=8.6633(2) Å, c=25.7280(8) Å, α=β=γ=90°, V=1287.83(7)A³. The formula weight of the asymmetric unit in the crystal structureis 245.75 g mol⁻¹ with Z=4, resulting in a calculated density of 1.267 gcm⁻³. The space group is determined to be P2₁2₁2₁. A summary of thecrystal data and crystallographic data collection parameters areprovided in Table 2 below.

The R-value is 0.033 (3.3%).

An ORTEP drawing of Crystalline Form A is shown in FIG. 18.

The asymmetric unit, shown in FIG. 18, contains a protonated(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane molecule and achloride counter ion. The proton is located in the difference map andallowed to refine freely on the nitrogen, indicating salt formation.

Packing diagrams viewed along the a, b, and c crystallographic axes areshown in FIGS. 19-21, respectively. Hydrogen bonding occurs between thechlorine and nitrogen atoms, and the structure consists of infiniteone-dimensional hydrogen bonded chains along the crystallographic aaxis, shown in FIG. 22.

The absolute structure can be determined through an analysis ofanomalous X-ray scattering by the crystal. A refined parameter x, knownas the Flack parameter (Flack, H. D.; Bernardinelli, G., Acta Cryst.,1999, A55, 908; Flack, H. D.; Bernardinelli, G., J. Appl. Cryst., 2000,33, 1143), encodes the relative abundance of the two components in aninversion twin. The structure contains a fraction 1-x of the model beingrefined, and x of its inverse. Provided that a low standard uncertaintyis obtained, the Flack parameter should be close to 0 if the solvedstructure is correct, and close to 1 if the inverse model is correct.The measured Flack parameter for the structure of Crystalline Form Ashown in FIG. 18 is −0.02 with a standard uncertainty of 0.06.

After a structure is solved the quality of the data may be assessed forits inversion-distinguishing power, which is done by an examination ofthe standard uncertainty of the Flack parameter. For Crystalline Form A,the standard uncertainty, (u), equals 0.06, which indicates stronginversion-distinguishing power. The compound is enantiopure and absolutestructure can be assigned directly from the crystal structure.

Refinement of the Flack parameter (x) (Flack, H. D. Acta Cryst. 1983,A39, 876) does not result in a quantitative statement about the absolutestructure assignment. However, an approach applying Bayesian statisticsto Bijvoet differences can provide a series of probabilities fordifferent hypotheses of the absolute structure (Hooft, R. W., J. Appl.Cryst., 2008, 41, 96-103; Bijvoet, J. M.; Peederman, A. F.; van Bommel,A. J., Nature 1951, 168, 271). This analysis provides a Flack equivalent(Hooft) parameter in addition to probabilities that the absolutestructure is either correct, incorrect or a racemic twin. For thecurrent data set the Flack equivalent (Hooft) parameter is determined tobe −0.01(3), the probability that the structure is correct is 1.000, theprobability that the structure is incorrect is 0.000 and the probabilitythat the material is a racemic twin is 0.4⁻⁵⁹.

The structure contains two chiral centers located at C11 and C15 (seeFIG. 18, ORTEP drawing), which are assigned as R and S configuration,respectively.

FIG. 23 shows a calculated X-ray powder diffraction pattern ofCrystalline Form A, generated from the single crystal data.

The experimental X-ray powder diffraction pattern of Crystalline Form Ais shown in FIG. 1.

The experimental XRPD of Crystalline Form A from FIG. 1 is overlaid withthe calculated pattern in FIG. 34.

Differences in intensities between the calculated and experimental x-raypowder diffraction patterns often are due to preferred orientation.Preferred orientation is the tendency for crystals to align themselveswith some degree of order. This preferred orientation of the sample cansignificantly affect peak intensities, but not peak positions, in theexperimental powder diffraction pattern. Furthermore, some shift in peakposition between the calculated and experimental powder diffractionpatterns may be expected because the experimental powder pattern iscollected at ambient temperature and the single crystal data iscollected at 150 K. Low temperatures are used in single crystal analysisto improve the quality of the structure but can contract the crystalresulting in a change in the unit cell parameters, which is reflected inthe calculated powder diffraction pattern. These shifts are particularlyevident at high diffraction angles.

Tables of positional parameters and their estimated standard deviations(Table 3), anisotropic temperature factor coefficients (Table 4), bonddistances (Table 5), bond angles (Table 6), hydrogen bonds and angles(Table 7) and torsion angles (Table 8) are provided below.

TABLE 2 Crystal Data and Data Collection Parameters for (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydro- chloride Form A(Crystalline Form A) formula C₁₅H₁₆ClN formula weight 245.75 space groupP2₁2₁2₁ (No. 19) a, Å 5.7779(2) b, Å 8.6633(2) c, Å 25.7280(8) V, Å³1287.83(7) Z 4 d_(calc), g cm⁻³ 1.267 crystal dimensions, mm 0.38 × 0.30× 0.18 temperature, K 150 radiation (wavelength, Å) Mo K_(α) (0.71073)monochromator graphite linear abs coef, mm⁻¹ 0.273 absorption correctionapplied empirical^(a) transmission factors: min, max 0.953, 0.953diffractometer Nonius Kappa CCD h, k, l range −7 to 7 −11 to 11 −33 to33 2θ range, deg 1.58-55.71 mosaicity, deg 0.38 programs used SHELXTLF₀₀₀ 520.0 weighting 1/[σ²(F_(o) ²) + (0.0384P)² + 0.2436P] where P =(F_(o) ² + 2F_(c) ²)/3 data collected 5812 unique data 2930 R_(int)0.029 data used in refinement 2930 cutoff used in R-factor calculationsF_(o) ² > 2.0σ(F_(o) ²) data with I > 2.0σ(I) 2678 number of variables162 largest shift/esd in final cycle 0.00 R(F_(o)) 0.033 R_(w)(F_(o) ²)0.080 goodness of fit 1.066 absolute structure determination Flackparameter^(b) (−0.02(6)) Hooft parameter^(c) (−0.01(3)) Friedel Coverage90% ^(a)Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276, 307.^(b)Flack, H. D. Acta Cryst., 1983 A39, 876. ^(c)Hooft, R. W. W.,Straver, L. H., and Spek, A. L. J. Appl. Cryst., 2008, 41, 96-103.

TABLE 3 Positional Parameters and Their Estimated Standard Deviationsfor Crystalline Form A Atom x y z U(Å²) Cl1 −0.21843(7) 1.09587(4)0.483829(15) 0.02856(9) N13 0.2878(3) 1.04618(14) 0.53004(5) 0.0234(3)C1 0.4183(3) 0.93704(19) 0.70605(6) 0.0294(4) C2 0.2847(3) 0.88296(17)0.66572(6) 0.0268(4) C3 0.0828(3) 0.7983(2) 0.67700(7) 0.0380(5) C40.0151(3) 0.7719(3) 0.72723(8) 0.0426(6) C5 0.1497(3) 0.8274(2)0.76923(7) 0.0340(5) C6 0.0855(4) 0.8007(3) 0.82173(8) 0.0465(6) C70.2208(4) 0.8543(2) 0.86149(7) 0.0483(6) C8 0.4249(4) 0.9340(2)0.85125(7) 0.0447(6) C9 0.4915(4) 0.9627(2) 0.80087(7) 0.0391(5) C100.3549(3) 0.9099(2) 0.75855(6) 0.0294(4) C11 0.3521(3) 0.91598(19)0.61066(6) 0.0261(4) C12 0.2704(3) 1.06743(16) 0.58785(5) 0.0270(4) C140.2577(3) 0.87808(16) 0.51906(6) 0.0282(4) C15 0.3409(3) 0.7984(2)0.56741(7) 0.0314(5) C16 0.5712(3) 0.8497(2) 0.58846(7) 0.0352(5) H1310.436(4) 1.082(2) 0.5177(8) 0.036(5)* H132 0.168(4) 1.105(2) 0.5138(7)0.039(5)* H1 0.555 0.993 0.699 0.035 H3 −0.008 0.759 0.649 0.046 H4−0.123 0.716 0.734 0.051 H6 −0.052 0.745 0.829 0.056 H7 0.175 0.8370.896 0.058 H8 0.519 0.969 0.879 0.054 H9 0.630 1.018 0.794 0.047 H150.285 0.692 0.575 0.038 H12A 0.109 1.089 0.598 0.032 H12B 0.370 1.1540.600 0.032 H14A 0.351 0.847 0.489 0.034 H14B 0.093 0.853 0.512 0.034H16A 0.659 0.776 0.610 0.042 H16B 0.667 0.918 0.566 0.042 Starred atomsare refined isotropically U_(eq) = (⅓)Σ_(i)Σ_(j)U_(ij)a*_(i)a*_(j)a_(i).a_(j) Hydrogen atoms are included in calculationof structure factors but not refined

TABLE 4 Anisotropic Temperature Factor Coefficients - U's forCrystalline Form A Name U(1,1) U(2,2) U(3,3) U(1,2) U(1,3) U(2,3) Cl10.02543(19) 0.02561(17) 0.03463(19) 0.00075(15) 0.00262(16) 0.00196(16)N13 0.0268(7) 0.0213(6) 0.0222(6) 0.0008(6) −0.0013(6) −0.0002(5) C10.0292(9) 0.0301(9) 0.0290(8) −0.0056(7) 0.0005(7) 0.0014(7) C20.0258(8) 0.0290(8) 0.0256(7) 0.0017(7) −0.0019(6) 0.0053(6) C30.0278(9) 0.0550(12) 0.0313(9) −0.0099(9) −0.0063(8) 0.0089(8) C40.0286(10) 0.0605(13) 0.0388(11) −0.0118(10) −0.0015(8) 0.0154(10) C50.0326(10) 0.0394(10) 0.0301(8) 0.0019(8) 0.0016(7) 0.0094(8) C60.0458(12) 0.0584(13) 0.0354(10) −0.0020(11) 0.0068(10) 0.0160(9) C70.0664(14) 0.0518(11) 0.0266(8) 0.0055(12) 0.0037(10) 0.0084(8) C80.0628(14) 0.0437(12) 0.0276(9) 0.0012(10) −0.0062(9) −0.0020(8) C90.0479(12) 0.0386(10) 0.0309(10) −0.0053(9) −0.0015(8) −0.0037(8) C100.0334(9) 0.0282(8) 0.0265(8) 0.0020(7) −0.0002(6) 0.0017(7) C110.0252(8) 0.0282(8) 0.0249(7) −0.0008(7) −0.0014(6) 0.0018(7) C120.0352(9) 0.0244(7) 0.0215(7) −0.0015(7) 0.0001(7) −0.0019(5) C140.0343(8) 0.0221(7) 0.0283(7) 0.0013(6) −0.0041(7) −0.0040(6) C150.0393(11) 0.0245(8) 0.0303(8) 0.0047(7) −0.0011(7) 0.0004(7) C160.0308(9) 0.0452(10) 0.0297(8) 0.0105(8) 0.0006(7) 0.0081(8) The form ofthe anisotropic temperature factor is: exp[−2πh²a*²U(1,1) +k²b*²U(2,2) + l²c*²U(3,3) + 2hka*b*U(1,2) + 2hla*c*U(1,3) +2klb*c*U(2,3)] where a*, b*, and c* are reciprocal lattice constants.

TABLE 5 Bond Distances in Angstroms for Crystalline Form A Atom 1 Atom 2Distance N13 C14 1.4936(18) N13 C12 1.5023(18) N13 H131 0.96(2) N13 H1320.96(2) C1 C2 1.376(2) C1 C10 1.419(2) C1 H1 0.950 C2 C3 1.408(2) C2 C111.497(2) C3 C4 1.370(3) C3 H3 0.950 C4 C5 1.415(3) C4 H4 0.950 C5 C101.412(3) C5 C6 1.420(3) C6 C7 1.369(3) C6 H6 0.950 C7 C8 1.391(3) C7 H70.950 C8 C9 1.375(3) C8 H8 0.950 C9 C10 1.420(3) C9 H9 0.950 C11 C161.503(2) C11 C15 1.510(2) C11 C12 1.513(2) C12 H12A 0.990 C12 H12B 0.990C14 C15 1.501(2) C14 H14A 0.990 C14 H14B 0.990 C15 C16 1.504(3) C15 H151.000 C16 H16A 0.990 C16 H16B 0.990 Numbers in parentheses are estimatedstandard deviations in the least significant digits.

TABLE 6 Bond Angles in Degrees for Crystalline Form A Atom 1 Atom 2 Atom3 Angle Atom 1 Atom 2 Atom 3 Angle C14 N13 C12 107.39(11) C5 C10 C1119.08(16) C14 N13 H131 110.6(12) C5 C10 C9 118.71(16) C12 N13 H131110.3(12) C1 C10 C9 122.21(17) C14 N13 H132 110.8(13) C2 C11 C16120.40(14) C12 N13 H132 108.7(12) C2 C11 C15 123.87(14) H131 N13 H132109.2(16) C16 C11 C15 59.90(12) C2 C1 C10 121.10(16) C2 C11 C12116.85(14) C2 C1 H1 119.50 C16 C11 C12 116.53(15) C10 C1 H1 119.50 C15C11 C12 106.60(13) C1 C2 C3 119.14(15) N13 C12 C11 104.89(12) C1 C2 C11120.17(15) N13 C12 H12A 110.80 C3 C2 C11 120.69(15) C11 C12 H12A 110.80C4 C3 C2 121.22(17) N13 C12 H12B 110.80 C4 C3 H3 119.40 C11 C12 H12B110.80 C2 C3 H3 119.40 H12A C12 H12B 108.80 C3 C4 C5 120.43(18) N13 C14C15 104.74(12) C3 C4 H4 119.80 N13 C14 H14A 110.80 C5 C4 H4 119.80 C15C14 H14A 110.80 C10 C5 C4 119.01(16) N13 C14 H14B 110.80 C10 C5 C6119.16(17) C15 C14 H14B 110.80 C4 C5 C6 121.82(18) H14A C14 H14B 108.90C7 C6 C5 120.4(2) C14 C15 C16 116.45(15) C7 C6 H6 119.80 C14 C15 C11108.31(14) C5 C6 H6 119.80 C16 C15 C11 59.81(11) C6 C7 C8 120.71(18) C14C15 H15 119.20 C6 C7 H7 119.60 C16 C15 H15 119.20 C8 C7 H7 119.60 C11C15 H15 119.20 C9 C8 C7 120.36(19) C11 C16 C15 60.29(12) C9 C8 H8 119.80C11 C16 H16A 117.70 C7 C8 H8 119.80 C15 C16 H16A 117.70 C8 C9 C10120.6(2) C11 C16 H16B 117.70 C8 C9 H9 119.70 C15 C16 H16B 117.70 C10 C9H9 119.70 H16A C16 H16B 114.90 Numbers in parentheses are estimatedstandard deviations in the least significant digits.

TABLE 7 Hydrogen Bond Distances in Angstroms and Angles in Degrees forCrystalline Form A D H A D-H A-H D-A D-H-A N13 H131 Cl1 0.96(2) 2.18(2)3.121(2) 164.1(15) N13 H132 Cl1 0.96(2) 2.36(2) 3.187(2) 144.0(15) N13H132 Cl1 0.96(2) 2.674(18) 3.1217(19) 109.2(14) Numbers in parenthesesare estimated standard deviations in the least significant digits.

TABLE 8 Torsion Angles in Degrees for Crystalline Form A Atom 1 Atom 2Atom 3 Atom 4 Angle C14 N13 C12 C11 28.20 (0.18) C12 N13 C14 C15 −27.51(0.18) C10 C1 C2 C3 −0.50 (0.25) C10 C1 C2 C11 178.63 (0.15) C2 C1 C10C5 −0.71 (0.25) C2 C1 C10 C9 179.13 (0.16) C1 C2 C3 C4 1.39 (0.26) C11C2 C3 C4 −177.73 (0.18) C1 C2 C11 C12 −85.92 (0.20) C1 C2 C11 C15 137.54(0.17) C1 C2 C11 C16 65.41 (0.21) C3 C2 C11 C12 93.19 (0.19) C3 C2 C11C15 −43.34 (0.24) C3 C2 C11 C16 −115.47 (0.18) C2 C3 C4 C5 −1.05 (0.30)C3 C4 C5 C6 −179.38 (0.20) C3 C4 C5 C10 −0.18 (0.30) C4 C5 C6 C7 179.21(0.21) C10 C5 C6 C7 0.02 (0.46) C4 C5 C10 C1 1.04 (0.26) C4 C5 C10 C9−178.80 (0.18) C6 C5 C10 C1 −179.74 (0.18) C6 C5 C10 C9 0.42 (0.27) C5C6 C7 C8 −0.85 (0.33) C6 C7 C8 C9 1.25 (0.30) C7 C8 C9 C10 −0.80 (0.29)C8 C9 C10 C1 −179.87 (0.17) C8 C9 C10 C5 −0.03 (0.25) C2 C11 C12 N13−160.97 (0.14) C15 C11 C12 N13 −17.56 (0.17) C16 C11 C12 N13 46.58(0.18) C2 C11 C15 C14 141.11 (0.16) C2 C11 C15 C16 −108.36 (0.18) C12C11 C15 C14 0.94 (0.18) C12 C11 C15 C16 111.47 (0.15) C16 C11 C15 C14−110.53 (0.16) C2 C11 C16 C15 114.01 (0.17) C12 C11 C16 C15 −94.57(0.15) N13 C14 C15 C11 16.15 (0.18) N13 C14 C15 C16 −48.59 (0.19) C14C15 C16 C11 96.68 (0.16) Numbers in parentheses are estimated standarddeviations in the least significant digits.

Example 3—Preparation of Crystalline Forms A Through F

Crystalline Form A through Form F are prepared as follows by usingCrystalline Form A obtained from Example 1 above. A variety ofcrystallization techniques are used, including evaporation, cooling,solvent/antisolvent precipitation, slurry, vapor stress, and vapordiffusion, as described above. The results are presented in Table 9below:

TABLE 9 XRPD Solvent Method^(a) Observations Result — 40° C./75% RH/7 doff-white solids, irregular, A B/E chloroform SE off-white solids,needles, A B/E chloroform/ VD/RT/7 d off-white solids, needles, Aheptane B/E chloroform/ VD/RT/7 d off-white solids, irregular, A tolueneB/E DCM SE off-white solids, needles, A + B B/E VS/RT/7 d off-whitesolids, irregular, A B/E slurry/RT/7 d off-white solids, needles, B (forXRPD B/E see pattern labeled B in FIG. 4 and FIGS. 5, 6, and 7; for DSCand TGA see FIG. 8) SC (40° C. to RT, off-white solids, needles, Brefrigerator/2 d, B/E freezer/8 d) CC (40° C. to dry milky solution Bice/IPA) freezer/9 d off-white solids, needles, B/E DCM/ACN VD/RT/7 doff-white solids, needles, A B/E DCM/MEK VD/RT/7 d off-white solids,needles, A B/E EtOH FE off-white solids, irregular, A + B B/E VS/RT/7 doff-white solids, irregular, A B/E slurry/RT/7 d off-white solids,irregular, A B/E SC (70° C. to RT, off-white solids, irregular, A + weakC refrigerator/2 d, B/E peaks freezer/8 d) CC (70° C. to dry milkysolution C + weak A ice/IPA) peaks freezer/2 d off-white solids,irregular, (~18.5, 20.7, B/E 25.7 °2θ) EtOH/acetone VD/RT/9 d no solids— acetone addition no solids EtOH/hexanes VD/RT/7 d off-white solids,irregular, A B/E EtOH/THF VD/RT/9 d no solids — HFIPA SE off-whitesolids, irregular, A + weak B B/E peaks HFIPA/IPE AS precipitationoff-white solids, irregular, A + weak B/E peak (~18.9 °2θ) HFIPA/THF ASprecipitation off-white solids, irregular, A B/E IPA FE off-whitesolids, irregular, A B/E slurry/RT/7 d off-white solids, irregular, AB/E SC (70° C. to RT, off-white solids, needles, C (for XRPDrefrigerator/2 d, B/E see pattern labeled freezer/7 d) C in FIG. 4, FIG.9, and pattern labeled G in FIG. 13; for DSC and TGA see FIG. 12)^(b) CC(70° C. to dry milky solution C + possible ice/IPA) weak A peakfreezer/2 d off-white solids, irregular, (~25.7 °2θ) B/E (after 22 daysof ambient storage: C + possible weak A peaks (~12.3, 15.4, 16.6, 20.7,25.7 °2θ, for XRPD see FIGS. 10 and 11)^(c) MeOH SE off-white solids,irregular, A B/E MeOH:acetone FE off-white solids, irregular, A (1:5)B/E MeOH/dioxane VD/RT/7 d off-white solids, needles, A B/E MeOH/EtOAcVD/RT/7 d plates, — single crystal MeOH/EtOAc VD/RT/7 d plates —MeOH/IPE VD/RT/7 d very thin plates, possible A single crystalMeOH:toluene FE off-white solids, needles, A (1:5) B/E 1-propanol FEoff-white solids, irregular, A B/E slurry/RT/7 d off-white solids,irregular, A B/E 1-propanol SC (70° C. to RT, off-white solids, needles,B refrigerator/2 d) B/E CC (70° C. to dry milky solution ice/IPA)freezer/2 d off-white solids, needles, B + weak A B/E and C peaks(~17.8, 18.5, 20.7 °2θ) TFE SE light-orange solids, A + weak Birregular, B/E peaks TFE/ACN AS precipitation off-white solids, needles,A B/E TFE/EtOAc AS precipitation off-white solids, needles, A B/ETFE/MEK AS precipitation off-white solids, needles, A B/E water FEoff-white solids, irregular, B B/E slurry/RT/7 d off-white solids,irregular, B B/E dioxane:water FE off-white solids, irregular, A (1:1)B/E ^(a)Reported temperatures, times, and RH value are approximate.bAbout 25 mg scale. Concentration of IPA solution: 10 mg/mL. ^(c)About27 mg scale. Concentration of IPA solution: 10 mg/mL.

Crystalline Form B—

As summarized above, Crystalline Form B is obtained from evaporation andslurry in water, slurry, slow and crash cooling in DCM, as well as slowcooling in 1-propanol. In addition, materials exhibiting XRPD patternsof Crystalline Form A with Crystalline Form B peaks result fromevaporation in DCM, ethanol, HFIPA, and TFE. Material exhibiting XRPDpattern of Crystalline Form B with weak Crystalline Form A andCrystalline Form C peaks is observed from a crash cooling experiment in1-propanol.

Crystalline Form B is indexed from a high-resolution XRPD pattern usingX'Pert High Score Plus (X'Pert High Score Plus 2.2a (2.2.1)) (FIG. 6,high-resolution XRPD pattern also shown in FIG. 7). The pattern appearsto represent a mixture of Crystalline Forms B and A. Agreement betweenthe allowed peak positions, marked with bars for the current form andthe observed peaks indicates a consistent unit cell determination. Peaksat 18.50, 20.7°, 25.7°, and 27.5° two-theta are not consistent with theindexing solution of Crystalline Form B and are likely from CrystallineForm A. Space groups consistent with the assigned extinction symbol,unit cell parameters, and derived quantities are tabulated below thefigure. To confirm the tentative indexing solution, the molecularpacking motifs within the crystallographic unit cell must be determined.No attempts at molecular packing are performed. Crystalline Form B isindexed with a similar volume per formula unit compared to CrystallineForm A, suggesting Crystalline Form B is an unsolvated crystalline form.

XRPD Data acquisition parameters for pattern labeled B in FIG. 4 andFIG. 5: INEL XRG-3000, X-ray Tube: 1.54187100 Å, Voltage: 40 (kV),Amperage: 30 (mA), Acquisition Time: 300 sec, Spinning capillary, Stepsize: approximately 0.03 °2θ.

XRPD Data acquisition parameters for FIGS. 6 and 7: Panalytical X-PertPro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 Å), Voltage: 45 kV,Amperage: 40 mA, Scan Range: 1.00-39.99 °2θ, Step Size: 0.017 °2θ,Collection Time: 1939 s, Scan Speed: 1.2°/min., Slit: DS: ½°, SS: null,Revolution Time: 1.0 s, Mode: Transmission.

Characterization data for Crystalline Form B are summarized in Table 10below:

TABLE 10 Analysis Result XRPD B (for XRPD see pattern labeled B in FIG.4 and FIG. 5) B + possible weak A peaks^(b) (~18.5, 20.7, 25.7, 27.5°2θ) (for XRPD see FIGS. 6 and 7) DSC^(a) 141° C. (endo, peak; 137° C.onset); 248° C. (endo, peak; 246° C. onset); 251° C. (endo, peak); 264°C. (endo, peak) (for DSC see FIG. 8) TGA^(a) 0.2% weight loss up to 200°C. 281° C. (onset, decomposition) (for TGA see FIG. 8) ^(a)Temperaturesare rounded to the nearest ° C.; weight loss values are rounded to onedecimal place. ^(b)High-resolution XRPD.

The thermal analysis results for Crystalline Form B are shown in FIG. 8(DSC, Size: 1.2600 mg, Method: (−30)-300-10, TOC; TGA, Size: 9.4320 mg,Method: 00-350-10). By TGA, Crystalline Form B exhibits a small weightloss of approximately 0.2% from ambient to 200° C., possibly due totrace amounts of solvent. The dramatic change in the slope of the TGAthermogram at approximately 281° C. is consistent with decomposition. ByDSC, a broad endotherm observed at approximately 141° C. (peak) issuspected to be attributed to either a solid form change or possibly aloss of volatiles on heating. Crystalline Form B displays an endothermat approximately 248° C. (peak), similar to the thermal behaviorobserved for Crystalline Form A, followed by two broad endotherms atapproximately 251 and 264° C. Based on the data obtained, CrystallineForm B is an unsolvated, crystalline material.

Crystalline Form C—

Crystalline Form C may be made by slow cooling in isopropanol. Materialexhibiting XRPD pattern of Crystalline Form A with weak Crystalline FormC peaks results from a slow cooling experiment in ethanol; while thecrash cooling experiments in ethanol and isopropanol afford XRPD patternCrystalline Form C with weak Crystalline Form A peaks.

Six scale-up attempts are conducted to prepare Crystalline Form C bycooling in isopropanol on approximately 50-150 mg scale (Table 11) andthe solids tested by XRPD. At refrigerator temperature, precipitatedsolids yield Form B. Seeding with Form C after cooling in therefrigerator (no solids observed) and before placing in the freezeryield XRPD pattern of Form C with B peaks. Precipitation at freezertemperature results in solids with an XRPD pattern of Form C with Apeaks. A solution placed in the freezer after cooling to roomtemperature with a lower concentration (7 mg/mL compared to 10 mg/mL)yields Form B. By crash cooling (ambient solution placed into dryice/isopropanol), solids generated are a mixture of Forms B and A. Thelast attempt on an approximate 50-mg scale generates a mixture of FormsA and C. The different outcomes of these experiments suggest possiblefactors affecting the crystallization of Form C on a larger scale (e.g.,concentration, temperature, cooling time, and seeding), and competitivecrystallization of Forms A and B that are possibly more stable under theexperimental conditions used. Note that Form C remains unchanged by XRPDafter 22 days of ambient storage.

XRPD Data acquisition parameters for patterns labeled A, C, and F inFIG. 13: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059Å), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2θ, StepSize: 0.017 °2θ, Collection Time: 717 s, Scan Speed: 3.3°/min., Slit:DS: ½°, SS: null, Revolution Time: 1.0 s, Mode: Transmission.

XRPD Data acquisition parameters for pattern labeled B in FIG. 13:Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 Å),Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2θ, Step Size:0.017 °2θ, Collection Time: 720 s, Scan Speed: 3.2°/min., Slit: DS: ½°,SS: null, Revolution Time: 1.0 s, Mode: Transmission.

XRPD Data acquisition parameters for pattern labeled D in FIG. 13:Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 Å),Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2θ, Step Size:0.017 °2θ, Collection Time: 718 s, Scan Speed: 3.3°/min., Slit: DS: ½°,SS: null, Revolution Time: 1.0 s, Mode: Transmission.

XRPD Data acquisition parameters for pattern labeled E in FIG. 13:Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54060 Å),Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99 °2θ, Step Size:0.017 °2θ, Collection Time: 720 s, Scan Speed: 3.2°/min., Slit: DS: ½°,SS: null, Revolution Time: 1.0 s, Mode: Transmission.

TABLE 11 Attempted XRPD material Solvent Method^(a) Observations ResultC IPA SC (70° C. to off-white B (for RT, solids, XRPD see refrigerator/2d) needles, B/E^(b) pattern labeled A in FIG. 13) SC (70° C. tooff-white C + B RT, solids, (for refrigerator/4 h, irregular & XRPD seefreezer/3 d) needles, pattern B/E^(c,d) labeled B in FIG. 13) SC (70° C.to off-white C + A RT, solids, (for refrigerator/4 h, irregular & XRPDsee freezer/2 d) needles, B/E^(c) pattern labeled C in FIG. 13) SC (70°C. to off-white B (for RT, freezer/7 d) solids, XRPD see irregular,B/E^(e) pattern labeled D in FIG. 13) CC (70° C. to off-white B + A dryice/IPA/4 h) solids, (for irregular, B/E^(c) XRPD see pattern labeled Ein FIG. 13) SC (70° C. to off-white A + C RT, solids, (forrefrigerator/4 h, irregular, B/E^(c) XRPD see freezer/3 d) patternlabeled F in FIG. 13) ^(a)Reported temperatures and times areapproximate. ^(b)Concentration of IPA solution: 11 mg/mL.^(c)Concentration of IPA solution: 10 mg/mL. ^(d)Seeded with CrystallineForm C (for XRPD of seeds see pattern labeled C in FIG. 4 and FIG. 9)before moving into the freezer. ^(e)Concentration of IPA solution: 7mg/mL.

Form C is indexed from a high-resolution XRPD pattern (FIG. 10) usingproprietary software. The pattern appears to represent a mixture ofForms C and A. Agreement between the allowed peak positions, marked withbars for the current form and the observed peaks indicates a consistentunit cell determination. Peaks at 12.3°, 15.4°, 16.6°, 20.7°, and 25.7°two-theta are not consistent with the indexing solution of Form C andare likely from Form A. Space groups consistent with the assignedextinction symbol, unit cell parameters, and derived quantities aretabulated below the figure. To confirm the tentative indexing solution,the molecular packing motifs within the crystallographic unit cell mustbe determined. No attempts at molecular packing are performed. Form C isindexed with a similar volume per formula unit compared to Form A,suggesting Form C is an unsolvated crystalline form.

XRPD Data acquisition parameters for pattern labeled C in FIG. 4, FIG.9, and pattern labeled G in FIG. 13: INEL XRG-3000, X-ray Tube:1.54187100 Å, Voltage: 40 (kV), Amperage: 30 (mA), Acquisition Time: 300sec, Spinning capillary, Step size: approximately 0.03 °2θ.

XRPD Data acquisition parameters for FIGS. 10 and 11: Panalytical X-PertPro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 Å), Voltage: 45 kV,Amperage: 40 mA, Scan Range: 1.00-39.99 °2θ, Step Size: 0.017 °2θ,Collection Time: 720 s, Scan Speed: 3.2°/min., Slit: DS: ½°, SS: null,Revolution Time: 1.0 s, Mode: Transmission.

Characterization data for Form C are summarized in Table 12 below:

TABLE 12 Analysis Result XRPD C (for XRPD see pattern labeled C in FIG.4, FIG. 9, and pattern labeled G in FIG. 13) DSC^(a) 122° C. (endo,peak; 112° C. onset); 248° C. (endo, peak; 246° C. onset; ΔH: 88 J/g);271° C. (endo, peak) (for DSC see FIG. 12) TGA^(a) 1.3% weight loss upto 200° C. 266° C. (onset, decomposition) (for TGA see FIG. 12) XRPD C +possible weak A peak (~25.7 °2θ) C + possible weak A peaks^(b) (for XRPDsee FIGS. 10 and 11) (~12.3, 15.4, 16.6, 20.7, 25.7 °2θ)^(a)Temperatures are rounded to the nearest ° C.; weight loss values arerounded to one decimal place; reported ΔH values are rounded to thenearest whole number. ^(b)High-resolution XRPD, reanalyzed after 22 daysof ambient storage.

The thermal analysis results for Form C are shown in FIG. 12 (DSC, Size:1.0100 mg, Method: (−30)-300-10, TOC; TGA, Size: 2.2300 mg, Method:00-350-10). By TGA, Form C exhibits a weight loss of approximately 1.3%from ambient to 200° C., possibly due to loss of volatiles upon heating.The dramatic change in the slope of the TGA thermogram at approximately266° C. is consistent with decomposition. By DSC, a broad smallendotherm observed at approximately 122° C. (peak) is suspected to beattributed to either a solid form change or possibly a loss of volatileson heating. Form C displays an endotherm at approximately 248° C.(peak), similar to the thermal behavior observed for Form A, followed bya broad endotherm at approximately 271° C.

Based on the data obtained, Form C is an unsolvated, crystallinematerial.

Crystalline Forms D, E, and F—

Crystalline Form A is dissolved in pH adjusted buffered media.Undissolved solid or precipitate observed is analyzed by XRPD. Someexperiments are conducted at elevated temperature to increasesolubility, the undissolved solids are also analyzed by XRPD. Theresulting Crystalline Forms D, E, and F are generated during theseexperiments as summarized in Table 13 below.

XRPD Data acquisition parameters for patterns labeled D-F in FIG. 14:INEL XRG-3000, X-ray Tube: 1.54187100 Å, Voltage: 40 (kV), Amperage: 30(mA), Acquisition Time: 300 sec, Spinning capillary, Step size:approximately 0.03° 20.

TABLE 13 XRPD pH Buffer Method^(a) Observations Result pH 2.0slurry/RT/7 d off-white solids, A (50 mM irregular, B/E KCl/HCl) SC (70°C. to off-white solids, A RT) irregular, B/E pH 4.4 spontaneousoff-white solids, D (50 mM citric precipitation irregular, B/Eacid/sodium slurry/RT/7 d off-white solids, B + weak citrate) irregular,B/E D peaks stir at 70° C./ off-white solids, D (for 30 min irregular,B/E XRPD see pattern labeled D in FIG. 14) pH 6.0 slurry/50° C./3 doff-white solids, E (50 mM irregular, B/E (contains Na₂HPO₄/NaH₂PO₄)peaks of F) (for XRPD see pattern labeled E in FIG. 14) pH 8.1 stir at70° C./ off-white solids, F (for (50 mM 30 min irregular, B/E XRPD seeNa₂HPO₄/NaH₂PO₄) pattern labeled F in FIG. 14) ^(a)Reported times andtemperatures are approximate.

-   -   pH 2.0 buffer (50 mM KCl/HCl): Crystalline Form A is recovered        from slow cooling (approximately 70° C. to ambient) and slurry        at room temperature.    -   pH 4.4 buffer (50 mM citric acid/sodium citrate): Crystalline        Form D results from spontaneous precipitation at room        temperature and after stirring a suspension at approximately 70°        C.; a room temperature slurry yields Crystalline Form B with        weak Crystalline Form D peaks by XRPD.    -   pH 6.0 buffer (50 mM Na₂HPO₄/NaH₂PO₄): Crystalline Form E with        peaks also found in Crystalline Form F by XRPD is observed from        slurry at approximately 50° C.    -   pH 8.1 buffer (50 mM Na₂HPO₄/NaH₂PO₄): Crystalline Form F        results from stirring a suspension at approximately 70° C.

Crystalline Forms D, E, and F are characterized by XRPD as shown in FIG.14.

Example 4—Amorphous

Attempts to prepare amorphous(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride areperformed by milling, lyophilization, and rotary evaporation (Table 14).Possible disordered Crystalline Form A materials are recovered from allattempts used in this study.

XRPD Data acquisition parameters for FIGS. 52-55: Bruker Discovery D8,X-ray Tube: Cu (1.54059 Å), Scan Range: 2.14-37.02 °2θ, Step Size: 0.04°2θ, Acquisition Time: 900 s.

TABLE 14 Conditions^(a) Observations Analysis Results freeze-dryingoff-white XRPD disordered in dioxane:water solids, A (for (1:1)/3 daggregates, XRPD see no B FIG. 51) freeze-drying off-white XRPDdisordered in water/3 d solids, A (for aggregates, XRPD see no B FIG.52) milling/30 Hz, off-white XRPD disordered 4 × 10 min solids, A (foraggregates, XRPD see no B FIG. 53) rotary off-white XRPD disorderedevaporation solids, A (for in HFIPA aggregates, XRPD see no B FIG. 54)^(a)Reported times are approximate.

Example 5—Preparation of Crystalline Form A

Commercially available reagents are used as received unless otherwisenoted. Reactions requiring an inert atmosphere are run under nitrogenunless otherwise noted.

Step 1 and 2:

MW d Compound (g/mol) (g/mL) Equivalents Amt/mol Reaction2-naphthylacetonitrile 167.21 NA 1.0 mol eq 4500 g/26.91 mol (SM)(S)-(+)-epichlorohydrin 92.52 3.12 1.30 mol eq 3200 g/34.58 moltetrahydrofuran 72.11 0.889 6.0 ml/g SM 32 L 2M sodiumbis(trimethylsilyl)amide  2.0M 0.916 2 mol eq 24700 g/5308 mol in THFborane-dimethylsulfide 10.0M 0.80 2.5 mol eq 6500 g/67 mol Isolation 2MHCl (aqueous)   2M NA 11.5 ml/g SM 57000 mL isopropyl acetate 102.130.872 4 mL/g SM as required water 18.02 1.00 5 mL/g SM as requiredammonia (aqueous) NA 0.889 1.5 mL/g SM 6300 mL 5% aqueous dibasic sodiumNA NA 4 mL/g SM 18000 mL phosphate para-toluenesulfonic acid 190.22 NA0.93 mol eq. 49000 g/8.34 mol monohydrate

2-naphthylacetonitrile (4500 g) is dissolved in THF (32 L), 3.2 kg of(S)-(+)-epichlorohydrin are added and the solution cooled to −16° C. A2.0 M solution of sodium hexamethyldisilylazane in tetrahydrofuran (THF)(24.7 kg) is then added, keeping the internal temperature below −10° C.This addition requires 2 hr 45 minutes to complete. The reaction mixtureis then stirred an additional six hours at approximately −15° C. afterwhich a sample is analyzed by HPLC. While keeping the internaltemperature less than 0° C., borane-dimethylsulfide (6.5 kg) is addedover 36 minutes. After completion of the borane addition, the reactionmixture is slowly heated to 60° C. to reduce the nitrile to the amine.During this heat-up, an exotherm is noted which initiates at 45° C.After heating at 60° C. for two hours a sample of the reaction mixtureis analyzed by HPLC. The reaction mixture is cooled to 24° C. andtransferred to a solution of 2M HCl over 1 hr. The two-phase mixture isheated to 50° C. and stirred for 1 hour at this temperature followed bycooling to 29° C. The pH of the quenched reaction mixture is measuredand found to be 5. Additional 2M HCl is added, the mixture heated to 50°C. and stirred for one hour, then cooled to 25° C. The pH is measuredand found to be 1. Reaction workup continues by the addition ofisopropyl acetate (IPAc), stirring, layer separation, and discard of theorganic layer. Aqueous ammonia is added to the aqueous layer and the pHmeasured, which shows a pH of 8. Additional ammonia is added and the pHre-measured and found to be 8.5. Workup then continues by extractionwith two extraction of the aqueous layer with IPAc. The combined organicextracts are then washed with 5% dibasic sodium phosphate in waterfollowed by a brine wash. The resulting organic layer is partiallyconcentrated to azeotropically dry followed by dilution with IPAc.p-Toluenesulfonic acid hydrate (4.9 kg) is then added in portions toprecipitate the desired product as its pTsOH salt, which is isolated byfiltration. The filtercake is washed with IPAc and then dried to aconstant weight to give 5785 g of the desired product as a white solid.Yield: 54%. HPLC: 98.2%.

Step 3 and 4:

MW d Compound (g/mol) (g/mL) Equivalents Amt/mol Reaction2-naphthylcyclopropylamine-tosylate 399.51 NA 1.0 mol eq 5785 g/145.18mol salt isopropylacetate 102.13 0.872 as required 176 L thionylchloride 118.97 1.638 1.2 eq 2.1 Kg/17.65 mol 5M NaOH 5.0M NA 6.0 moleq. 16.7 Kg Isolation magnesium sulfate NA NA 0.5 g/g 2.9 Kg hydrogenchloride in isopropyl alcohol 5.7M NA 1.0 mol eq. 0.90 L isopropylalcohol 60.1 0.786 1.5 mL/g as required Ethyl alcohol 200 (specialindustrial 80.25 0.786 1.5 mL/g as required denatured)

Step 3:

The amine-pTsOH salt (5785 g) obtained from step 2 is suspended in IPAc(176 L) to give a slurry. Thionyl chloride (2.1 kg) is then added overone hour. Upon completion of the thionyl chloride addition the reactionmixture is stirred one additional hour and a sample is analysed by HPLC.Aqueous sodium hydroxide (5M, 6 mol equivalents) is added over one hourfollowed by four hours of additional stirring. The layers are allowed tosettle and the pH of the aqueous layer is found to be 9. The layers areseparated and the organic layer washed with 1M NaOH in water. Theaqueous layers are combined and back extracted with IPAc and the initialorganic layer and the back extract combined. These combined organiclayers are washed with 0.5M HCl to extract(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane into the aqueouslayer. The acidic aqueous layer is washed with a 1:1 mixture of IPAc andTHF to remove color. The aqueous layer is basified with aqueous ammoniafollowed by extraction with IPAc. After layer separation the organiclayer is washed with brine, dried over magnesium sulfate, and partiallyconcentrated. After the concentration, hydrogen chloride in isopropylalcohol (IPA) (1.0 mol equivalent of HCl, 0.90 L) is added to form thecrude salt, which is isolated by filtration, washed with IPAc and thenpartially dried. The wet cake is refluxed in IPAc. The crude salt isrefluxed in IPA and the solids isolated by filtration, washed with IPA,and then dried. >99.5 HPLC area percent and 97.7% chiral area percentpurity. 1759 g of the desired product.

Step 4:

The crude (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexanehydrochloride (1753 g) obtained from step 3 is dissolved in 20 volumesof hot ethanol (70° C.) and then filtered via an inline filter as apolish filtration. The dissolution vessel and the inline filter andtransfer line are then rinsed with additional hot ethanol (61° C.) andthe rinse combined with the filtrate. The combined filtrate and washesare partially concentrated in vacuo to approximately 11.5 total volumes(relative to crude (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexanehydrochloride input) and then reheated to redissolve the solids. Thesolution is cooled to 65° C. and seed crystals added as slurry inethanol. After stirring at approx. 65° C. to develop the seed bed, theslurry is cooled to room temperature. The resulting solids are isolatedby filtration, the filtercake is washed with ethanol, and the washedsolids dried. A total of 1064 g of tan product is obtained. >99.5% forboth chiral and achiral HPLC.

Step 5:

The (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride(1064 g) obtained from step 4 is dissolved in 10.7 L of water whilewarming to 35° C. Once all solids dissolve, the aqueous solution iswashed with 1:1 THF:IPAc to remove most of the color. After the wash,aqueous ammonia is added to the aqueous layer and(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is extracted intoIPAc. The organic layer is dried over magnesium sulfate and thenconcentrated in vacuo to give an off-white solid. The solid is dissolvedin IPA and transferred to a 22 L 3-neck round bottom flask via inlinefiltration. Filtered hydrogen chloride in IPA is then added to reformthe salt, which is isolated via filtration. The filtercake is washedwith IPA and then dried to give 926 g of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride as aslightly off-white solid.

An XRPD of the product is shown in FIG. 35 and is consistent withCrystalline Form A. The XRPD pattern is collected with a PANalyticalX'Pert PRO MPD diffractometer using an incident beam of Cu radiationproduced using an Optix long, fine-focus source. An elliptically gradedmultilayer mirror is used to focus Cu Kα X-rays through the specimen andonto the detector. Prior to the analysis, a silicon specimen (NIST SRM640d) is analyzed to verify the observed position of the Si 111 peak isconsistent with the NIST-certified position. A specimen of the sample issandwiched between 3-μm-thick films and analyzed in transmissiongeometry. A beam-stop, short anti-scatter extension, and an anti-scatterknife edge are used to minimize the background generated by air. Sollerslits for the incident and diffracted beams are used to minimizebroadening from axial divergence. The diffraction pattern is collectedusing a scanning position-sensitive detector (X'Celerator) located 240mm from the specimen and Data Collector software v. 2.2b. Dataacquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-rayTube: Cu (1.54059 Å), Voltage: 45 kV, Amperage: 40 mA, Scan Range:1.00-39.99 °2θ, Step Size: 0.017 °2θ, Collection Time: 717 s, ScanSpeed: 3.3°/min., Slit: DS: ½°, SS: null, Revolution Time: 1.0 s, Mode:Transmission.

FIG. 36 overlays the XRPD patterns from FIG. 1 and FIG. 35. There aresome differences in relative peak intensities that are likely due topreferred orientation (PO). PO is the tendency for crystals, usuallyplates or needles, to pack against each other with some degree of order.PO can affect peak intensities, but not peak positions, in XRPDpatterns.

An XRPD of the product after long-term storage is shown in FIG. 37 andis consistent with Crystalline Form A. The XRPD pattern is collectedwith a PANalytical X'Pert PRO MPD diffractometer using an incident beamof Cu radiation produced using an Optix long, fine-focus source. Anelliptically graded multilayer mirror is used to focus Cu Kα X-raysthrough the specimen and onto the detector. Prior to the analysis, asilicon specimen (NIST SRM 640e) is analyzed to verify the observedposition of the Si 111 peak is consistent with the NIST-certifiedposition. A specimen of the sample is sandwiched between 3-μm-thickfilms and analyzed in transmission geometry. A beam-stop, shortantiscatter extension, and antiscatter knife edge are used to minimizethe background generated by air. Soller slits for the incident anddiffracted beams are used to minimize broadening from axial divergence.The diffraction pattern is collected using a scanning position-sensitivedetector (X'Celerator) located 240 mm from the specimen and DataCollector software v. 2.2b. Data acquisition parameters are: PanalyticalX-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu (1.54059 Å), Voltage: 45 kV,Amperage: 40 mA, Scan Range: 1.00-39.99 °2θ, Step Size: 0.017 °2θ,Collection Time: 719 s, Scan Speed: 3.3°/min., Slit: DS: ½°, SS: null,Revolution Time: 1.0 s, Mode: Transmission.

One PANalytical pattern is analyzed for Crystalline Form A, andpreferred orientation and particle statistic effects are assessedthrough comparison with additional XRPD patterns analyzed usingalternate geometry in addition to a calculated XRPD pattern from singlecrystal analysis. An indexing result for the XRPD shown in FIG. 37collected with Cu Kα radiation is shown in FIG. 38. The XRPD pattern isindexed using X'Pert High Score Plus 2.2a (2.2.1). Observed peaks areshown in FIG. 39 and listed in Table C in formula 1.32 above,representative peaks are listed in Table B in formula 1.25 above, andcharacteristic peaks are listed in Table A in formula 1.16 above.

Example 6—Preparation of Crystals of Form B Example 6a

558.9 mg of Crystalline Form A from Example 5 above is slurried in 5 mLdichloromethane. The preparation is stirred (300 RPM) in a sealed vialat ambient temperature for 16 days. White solids are isolated by vacuumfiltration, rinsed with 1 mL of dichloromethane, and briefly dried undernitrogen. Product is Crystalline Form A. An XRPD pattern of the productis in FIG. 47. The XRPD pattern is collected with a PANalytical X'PertPRO MPD diffractometer using an incident beam of Cu radiation producedusing an Optix long, fine-focus source. An elliptically gradedmultilayer mirror is used to focus Cu Kα X-rays through the specimen andonto the detector. Prior to the analysis, a silicon specimen (NIST SRM640e) is analyzed to verify the observed position of the Si 111 peak isconsistent with the NIST-certified position. A specimen of the sample issandwiched between 3-μm-thick films and analyzed in transmissiongeometry. A beam-stop, short antiscatter extension, and an antiscatterknife edge are used to minimize the background generated by air. Sollerslits for the incident and diffracted beams are used to minimizebroadening from axial divergence. Diffraction patterns are collectedusing a scanning position-sensitive detector (X'Celerator) located 240mm from the specimen and Data Collector software v. 2.2b. Dataacquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-rayTube: Cu (1.54059 Å), Voltage: 45 kV, Amperage: 40 mA, Scan Range:1.00-39.99 °2θ, Step Size: 0.017 °2θ, Collection Time: 720 s, ScanSpeed: 3.2°/min., Slit: DS: ½°, SS: null, Revolution Time: 1.0 s, Mode:Transmission.

Example 6b

34.3 mg of Crystalline Form A from Example 6a is contacted with 1 mL ofwater. The sample is sonicated until solids dissolve. The sample iscapped and left at ambient temperature until nucleation is observed,within one day. Singles are isolated from the bulk sample for analysis.

Data Collection: A colorless plate of C₁₅Hl₁₆ClN [C₁₅H₁₆N, Cl], havingapproximate dimensions of 0.31×0.21×0.09 mm, is mounted on a nylon loopin random orientation. Preliminary examination and data collection areperformed with Cu Kα radiation (λ =1.54178 Å) on a Rigaku Rapid IIdiffractometer equipped with confocal optics. Refinements are performedusing SHELX2014 (Sheldrick, G. M. Acta Cryst. 2015, C71, 3-8). Cellconstants and an orientation matrix for data collection are obtainedfrom least-squares refinement using the setting angles of 22958reflections in the range 2°<θ<26°. From the systematic presence of thefollowing conditions: h00 h=2n; 0k0 k=2n; 00ll=2n, and from subsequentleast-squares refinement, the space group is determined to be P2₁2₁2₁(no. 19). The data are collected to a maximum diffraction angle (2θ) of144.79°, at a temperature of 100 K.

Data Reduction: Frames are integrated with HKL3000 (Otwinowski, Z.;Minor, W. Methods Enzymol. 1997, 276, 307). A total of 22958 reflectionsare collected, of which 2415 are unique. Lorentz and polarizationcorrections are applied to the data. The linear absorption coefficientis 2.422 mm⁻¹ for Cu Kα radiation. An empirical absorption correctionusing SCALEPACK (Otwinowski, Z.; Minor, W. Methods Enzymol. 1997, 276,307) is applied. Transmission coefficients range from 0.753 to 0.976. Asecondary extinction correction is applied (Sheldrick, G. M. Acta Cryst.2015, C71, 3-8). The final coefficient, refined in least-squares, is0.0055(8) (in absolute units). Intensities of equivalent reflections areaveraged. The agreement factor for the averaging is 4.95% based onintensity.

Structure Solution and Refinement: The structure is solved by directmethods using SHELXS-97 (Sheldrick, G. M. Acta Cryst. 2015, C71, 3-8).The remaining atoms are located in succeeding difference Fouriersyntheses. Hydrogen atoms are included in the refinement but restrainedto ride on the atom to which they are bonded. The structure is refinedin full-matrix least-squares by minimizing the function:Σw(|F _(o)|² −|F _(c)|²)²The weight w is defined as 1/[σ²(F_(o) ²)+(0.0437P)²+(2.1802P)], whereP=(F_(o) ²+2F_(c) ²)/3. Scattering factors are taken from the“International Tables for Crystallography” (International Tables forCrystallography, Vol. C, Kluwer Academic Publishers: Dordrecht, theNetherlands, 1992, Tables 4.2.6.8 and 6.1.1.4). Of the 2415 reflectionsused in the refinements, only the reflections with F_(o) ²>2σ(F_(o) ²)are used in calculating the fit residual, R. A total of 2372 reflectionsare used in the calculation. The final cycle of refinement includes 155variable parameters and converges with unweighted and weighted agreementfactors of:R=Σ|F _(o) −F _(c) |/ΣF _(o)=0.033R _(w)=(Σw(F _(o) ² −F _(c) ²)² /Σw(F _(o) ²)²)=0.080

The standard deviation of an observation of unit weight (goodness offit) is 1.150. The highest peak in the final difference Fourier has aheight of 0.318 e/Å³. The minimum negative peak has a height of −0.313e/Å³.

Calculated X-ray Powder Diffraction (XRPD) Pattern: A calculated XRPDpattern is generated for Cu radiation using Mercury (Macrae, C. F.;Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.;Towler, M.; and van de Streek, J., J. Appl. Cryst., 2006, 39, 453-457)and the atomic coordinates, space group, and unit cell parameters fromthe single crystal structure. Because the single crystal data arecollected at low temperatures (100 K), peak shifts may be evidentbetween the pattern calculated from low temperature data and the roomtemperature experimental powder diffraction pattern, particularly athigh diffraction angles. The calculated XRPD pattern is adjusted to roomtemperature using the previously obtained unit cell parameters from XRPDindexing.

Atomic Displacement Ellipsoid and Packing Diagrams: The atomicdisplacement ellipsoid diagram is prepared using Mercury (Macrae, C. F.;Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.;Towler, M.; and van de Streek, J., J. Appl. Cryst., 2006, 39, 453-457).Atoms are represented by 50% probability anisotropic thermal ellipsoids.Packing diagrams and additional figures are prepared using Mercury.Hydrogen bonding is represented as dashed lines. Assessment of chiralcenters is performed with PLATON (Spek, A. L. PLATON. Molecular GraphicsProgram. Utrecht University, Utrecht, The Netherlands, 2008. Spek, A.L., J. Appl. Cryst. 2003, 36, 7). Absolute configuration is evaluatedusing the specification of molecular chirality rules (Cahn, R. S.;Ingold, C; Prelog, V. Angew. Chem. Intern. Ed. Eng., 1966, 5, 385 andPrelog, V., Helmchen, G. Angew. Chem. Intern. Ed. Eng., 1982, 21, 567).

Results: The orthorhombic cell parameters and calculated volume are:a=5.9055(2) Å, b=7.4645(3) Å, c=29.1139(13) A (α=β=γ=90°), V=1283.39(9)Å³. The formula weight of the asymmetric unit in Crystalline Form B is245.74 g mol⁻¹ with Z=4, resulting in a calculated density of 1.272 gcm⁻³. The space group is determined to be P2₁2₁2₁ (no. 19). A summary ofthe crystal data and crystallographic data collection parameters areprovided in Table 15 below. The space group and unit cell parameters areconsistent with those obtained for Form B by XRPD indexing.

The R value is 0.0453 (4.53%).

An atomic displacement ellipsoid drawing of Crystalline Form B is shownin FIG. 24.

The asymmetric unit shown in FIG. 24 contains one protonated(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane molecule and onechloride counter ion.

Packing diagrams viewed along the a, b, and c crystallographic axes areshown in FIGS. 25-27, respectively. Hydrogen bonding occurs from theamine to the chloride, forming one-dimensional hydrogen bonded helicalchains along the a axis, shown in FIG. 28.

The molecular conformation of the(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane molecules in thestructure of Crystalline Form B is compared with the molecularconformation observed in the structure of Crystalline Form A in FIG. 29,and the packing of the two forms viewed along the a axis is compared inFIG. 30. The hydrogen bonding in the structures of Crystalline Forms Aand B is shown in FIG. 31. Adjacent molecules are linked throughchloride ions in the Crystalline Form A hydrogen bonding formingstraight chains down the a axis. The amine groups of adjacent moleculesare too far apart in the Crystalline Form B packing to be linked in asimilar manner, and instead the hydrogen bonding in Crystalline Form Bforms a helical chain.

The absolute structure can be determined through an analysis ofanomalous X-ray scattering by the crystal. A refined parameter x, knownas the Flack parameter (Flack, H. D.; Bernardinelli, G., Acta Cryst.1999, A55, 908; Flack, H. D., Bernardinelli, G., J. Appl. Cryst. 2000,33, 1143, Flack, H. D., Acta Cryst. 1983, A39, 876; Parsons, S.; Flack,H. D.; Wagner, T., Acta Cryst. 2013, B69, 249-259), encodes the relativeabundance of the two components in an inversion twin. The structurecontains a fraction 1-x of the model being refined, and x of itsinverse. Provided that a low standard uncertainty is obtained, the Flackparameter should be close to 0 if the solved structure is correct, andclose to 1 if the inverse model is correct. The measured Flack parameterfor the structure of Crystalline Form B shown in FIG. 24 is 0.010 with astandard uncertainty of 0.010, which indicates stronginversion-distinguishing power. The compound is enantiopure and theabsolute configuration can be assigned directly from the crystalstructure.

Refinement of the Flack parameter (x) does not result in a quantitativestatement about the absolute structure assignment. However, an approachapplying Bayesian statistics to Bijvoet differences can provide a seriesof probabilities for different hypotheses of the absolute structure(Hooft, R. W. W.; Straver, L. H.; and Spek, A. L., J. Appl. Cryst.,2008, 41, 96-103 and Bijvoet, J. M.; Peerdeman, A. F.; van Bommel, A.J., Nature, 1951, 168, 271). This analysis provides a Flack equivalent(Hooft) parameter in addition to probabilities that the absolutestructure is either correct, incorrect or a racemic twin. For thecurrent data set the Flack equivalent (Hooft) parameter is determined tobe −0.001(7), the probability that the structure is correct is 1.000,the probability that the structure is incorrect is 0.000 and theprobability that the material is a racemic twin is 0.000.

This structure contains two chiral centers located at C2 and C3 (referto FIG. 24), which bond in the S and R configuration, respectively.

FIG. 32 shows a calculated XRPD pattern of Crystalline Form B, generatedfrom the single crystal structure.

An experimental XRPD pattern of Crystalline Form B is shown in FIG. 33(same as XRPD pattern in FIG. 40, Example 8), overlaid with thecalculated pattern and a calculated pattern that has been adjusted toroom temperature. All peaks in the experimental patterns are representedin the calculated XRPD pattern, indicating a single phase.

Differences in intensities between the calculated and experimentalpowder diffraction patterns often are due to preferred orientation.Preferred orientation is the tendency for crystals to align themselveswith some degree of order. This preferred orientation of the sample cansignificantly affect peak intensities, but not peak positions, in theexperimental powder diffraction pattern. Furthermore, some shift in peakposition between the calculated and experimental powder diffractionpatterns may be expected because the experimental powder pattern iscollected at ambient temperature and the single crystal data arecollected at 100 K. Low temperatures are used in single crystal analysisto improve the quality of the structure but can contract the crystalresulting in a change in the unit cell parameters, which is reflected inthe calculated powder diffraction pattern. These shifts are particularlyevident at high diffraction angles. The calculated XRPD pattern has beenadjusted to room temperature using the unit cell obtained previouslyfrom XRPD indexing.

TABLE 15 Crystal Data and Data Collection Parameters for(1R,5S)-1-(naphthalen-2- yl)-3-azabicyclo[3.1.0]hexane hydrochlorideForm B (Crystalline Form B) Empirical formula C₁₅H₁₆ClN Formula weight245.74 Temperature 100(2) K Wavelength 1.54178 Å Crystal systemOrthorhombic Space group P2₁2₁2₁ Unit cell dimensions a = 5.9055(2) Å α= 90°. b = 7.4645(3) Å β = 90°. c = 29.1139(13) Å γ = 90°. Volume1283.39(9) Å³ Z 4 Density (calculated) 1.272 Mg/m³ Absorptioncoefficient 2.422 mm⁻¹ F(000) 520 Crystal size 0.310 × 0.210 × 0.090 mm³Theta range for data collection 6.080 to 72.393°. Index ranges −7 <= h<= 7, −8 <= k <= 8, −35 <= l <= 35 Reflections collected 22958Independent reflections 2415 [R(int) = 0.0495] Completeness to theta =67.679° 98.5% Absorption correction Semi-empirical from equivalents Max.and min. transmission 0.976 and 0.753 Refinement method Full-matrixleast-squares on F² Data/restraints/parameters 2415/0/155Goodness-of-fit on F² 1.150 Final R indices [I > 2sigma(I)] R1 = 0.0453,wR2 = 0.1224 R indices (all data) R1 = 0.0464, wR2 = 0.1240 Absolutestructure parameter Flack parameter: 0.010(10) Hooft parameter:−0.001(7) Extinction coefficient 0.0055(8) Largest diff. peak and hole0.318 and −0.313 e · Å⁻³

Example 7—Preparation of Crystalline Form B

470.9 mg of Crystalline Form A from Example 5 above is mixed with 5 mLof water in a 20 mL glass vial. The slurry is stirred at ambienttemperature for 16 days with a stir bar to allow conversion to occur.The solids are collected by vacuum filtration and briefly dried undernitrogen.

Example 8—Preparation of Crystalline Form B

1 g of the product from Example 16 below is stirred in 5 mL of SpecialIndustrial 200 (ethanol denatured) over weekend at ambient temperature.The mixture is filtered and rinsed with 2 mL of Special Industrial 200(ethanol denatured) and followed by isopropyl acetate (2×3 mL). Pull drythe solids over 2 hours and then dry at 40° C. over 6 hours to give 0.81g of product.

An XRPD shows the product is Crystalline Form B (FIG. 40 and also shownas the top XRPD pattern in FIG. 33). The XRPD pattern is collected witha PANalytical X'Pert PRO MPD diffractometer using an incident beam of Curadiation produced using an Optix long, fine-focus source. Anelliptically graded multilayer mirror is used to focus Cu Kα X-raysthrough the specimen and onto the detector. Prior to the analysis, asilicon specimen (NIST SRM 640d) is analyzed to verify the observedposition of the Si 111 peak is consistent with the NIST-certifiedposition. A specimen of the sample is sandwiched between 3-μm-thickfilms and analyzed in transmission geometry. A beam-stop, shortanti-scatter extension, and an anti-scatter knife edge are used tominimize the background generated by air. Soller slits for the incidentand diffracted beams are used to minimize broadening from axialdivergence. The diffraction pattern is collected using a scanningposition-sensitive detector (X'Celerator) located 240 mm from thespecimen and Data Collector software v. 2.2b. Data acquisitionparameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu(1.54059 Å), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.01-39.98°2θ, Step Size: 0.017 °2θ, Collection Time: 720 s, Scan Speed:3.2°/min., Slit: DS: ½°, SS: null, Revolution Time: 1.0 s, Mode:Transmission.

One PANalytical pattern is analyzed for this material, and preferredorientation and particle statistic effects are assessed throughcomparison with additional XRPD patterns analyzed using alternategeometry in addition to a calculated XRPD pattern from single crystalanalysis. An indexing result for the XRPD shown in FIG. 40 collectedwith Cu Kα radiation is shown in FIG. 41. The XRPD pattern is indexedusing X'Pert High Score Plus 2.2a (2.2.1). Observed peaks are shown inFIG. 42 and listed in Table F in formula 1.109, representative peaks arelisted in Table E in formula 1.102, and characteristic peaks are listedin Table D in formula 1.93.

Example 9—Crystalline Form C

A turbid solution containing 458.2 mg of Crystalline Form A from Example5 and 40 mL of IPA is generated at elevated temperature. The hotsolution is filtered with a 0.2-μm nylon filter into a clean vial andplaced into a freezer. After two days, the solids are recovered byvacuum filtration and briefly dried under nitrogen. The solids areidentified as a mixture of Crystalline Forms A and C. A slurry isgenerated with 42.2 mg of the mixture and 0.8 mL of a saturated DCMsolution. (The saturated solution is generated with 65.4 mg ofCrystalline Form A from Example 5 in 5 mL of DCM at ambient temperature.Excess solids are filtered from the solution the following day with a0.2-μm nylon filter.) The slurry is stirred, 100 RPM, with an agate ballat 2° C. for 3 weeks to allow conversion to occur. Solids isolated fromthe resulting suspension through vacuum filtration are stored at atemperatures between −25 and −10° C.

An XRPD of the product is shown in FIG. 43. The XRPD pattern iscollected with a PANalytical X'Pert PRO MPD diffractometer using anincident beam of Cu radiation produced using an Optix long, fine-focussource. An elliptically graded multilayer mirror is used to focus Cu KαX-rays through the specimen and onto the detector. Prior to theanalysis, a silicon specimen (NIST SRM 640d) is analyzed to verify theobserved position of the Si 111 peak is consistent with theNIST-certified position. A specimen of the sample is sandwiched between3-μm-thick films and analyzed in transmission geometry. A beam-stop,short anti-scatter extension, and an anti-scatter knife edge are used tominimize the background generated by air. Soller slits for the incidentand diffracted beams are used to minimize broadening from axialdivergence. The diffraction pattern is collected using a scanningposition-sensitive detector (X'Celerator) located 240 mm from thespecimen and Data Collector software v. 2.2b. Data acquisitionparameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu(1.54059 Å), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99°2θ, Step Size: 0.017 °2θ, Collection Time: 720 s, Scan Speed:3.2°/min., Slit: DS: ½°, SS: null, Revolution Time: 1.0 s, Mode:Transmission.

One PANalytical pattern is analyzed for this material, and preferredorientation and particle statistic effects are assessed throughcomparison with additional XRPD patterns analyzed using alternategeometry. An indexing result for the XRPD pattern shown in FIG. 43collected with Cu Kα radiation is shown in FIG. 44. The XRPD pattern isindexed using proprietary software (U.S. Pat. No. 8,576,985). Observedpeaks are shown in FIG. 45 and listed in Table I in formula 1.183,representative peaks are listed in Table H in formula 1.176, andcharacteristic peaks are listed in Table G in formula 1.168.

Example 10—Interconversion Slurry Experiments

An Energy—Temperature Diagram is a semi-quantitative graphical solutionof the Gibbs-Helmholtz equation, where the enthalpy (H) and free energy(G) isobars for each form are depicted as a function of temperature. Thegraph assumes that the free energy isobars intersect at most once and,second, that the enthalpy isobars of the polymorphs do not intersect.The melting point of a polymorph is defined as the temperature at whichthe free energy isobar of the polymorph intersects the free energyisobar of the liquid. The transition temperature is defined as thetemperature at which the free energy isobar of one polymorph intersectsthe free energy isobar of the second. Thus, at T_(t) both polymorphshave equal free energy, and consequently are in equilibrium with eachother.

The proposed Energy—Temperature Diagram for Crystalline Forms A, B, andC is shown in FIG. 46. In the diagram, the enthalpy (H) and free energy(G) isobars for each form are depicted as a function of temperature (T).Subscripts A, B, C, and L refer to Crystalline Forms A, B, C, and liquidphase, respectively. Subscripts f, t, and m refer to fusion, transitionpoint, and melting point, respectively. The graph assumes that the freeenergy isobars intersect at most once and, second, that the enthalpyisobars of the polymorphs do not intersect. The melting point of apolymorph is defined as the temperature at which the free energy isobarof the polymorph intersects the free energy isobar of the liquid. Thetransition temperature is defined as the temperature at which the freeenergy isobar of one polymorph intersects the free energy isobar of thesecond. Thus, at T_(t) both polymorphic forms have equal free energy,and consequently are in equilibrium with each other. Crystalline Form Cis the stable solid phase below T_(t,C→B) (because the free energy ofCrystalline Form C is lower than that of Crystalline Form B),Crystalline Form B is the stable solid phase between T_(t,C→B) andT_(t,B→A), and Crystalline Form A is the stable solid phase aboveT_(t,B→A). The low energy polymorph will have a lower fugacity, vaporpressure, thermodynamic activity, solubility, dissolution rate per unitsurface area, and rate of reaction relative to the other polymorphs.

Interconversion experiments are performed to test the hypotheticalthermodynamic relationship between materials illustrated by theEnergy—Temperature Diagram above. Interconversion or competitive slurryexperiments are a solution-mediated process that provides a pathway forthe less soluble (more stable) crystal to grow at the expense of themore soluble crystal form (Bernstein, J. Polymorphism in MolecularCrystals. Clarendon Press, Oxford, 2006; Brittain, H. G., Polymorphismin Pharmaceutical Solids. Marcel Dekker, Inc., New York, 1999). Outsidethe formation of a solvate or degradation, the resulting more stablepolymorph from an interconversion experiment is independent of thesolvent used because the more thermodynamically stable polymorph has alower energy and therefore lower solubility. The choice of solventaffects the kinetics of polymorph conversion and not the thermodynamicrelationship between polymorphic forms (Gu, C. H., Young, V. Jr., Grant,D. J., J. Pharm. Sci. 2001, 90 (11), 1878-1890).

Binary interconversion slurry experiments between Crystalline Forms A,B, and C in different solvent systems at temperatures spanningapproximately 2 through 67° C. are summarized in Table 16 below.Saturated solutions are generated and then added to mixtures composed ofapproximately equivalent quantities of two of the polymorphs. Thesamples are slurried from overnight to three weeks and the solidsharvested and analyzed by XRPD. The results of the interconversionstudies indicate that the relative thermodynamic stability of theenantiotropes Crystalline Forms A, B, and C are correctly depicted bythe proposed Energy-Temperature Diagram. In addition, T_(t,C→B) isexpected below 2° C. (is not determined), T_(t,C→A) will be between 2°C. and ambient temperature, and T_(t,B→A) will be between 37 and 54° C.

TABLE 16 Binary Interconversion Slurries between Crystalline Forms A, B,and C Crystalline Forms Results Temp¹ Duration¹ Solvent (v/v) B + A B 2°C. 3 weeks DCM B 2° C. 3 weeks EtOH B + C B 2° C. 3 weeks DCM B 2° C. 3weeks EtOH C + A C 2° C. 3 weeks DCM C + A↓² 2° C. 3 weeks EtOH B + A Bambient 2 weeks DCM B ambient 2 weeks EtOH B ambient 2 weeks 10:1ACN/H₂O B + C B ambient 2 weeks DCM B ambient 2 weeks EtOH B ambient 2weeks 10:1 ACN/H₂O A + C A ambient 2 weeks DCM A ambient 2 weeks EtOH B³ambient 2 weeks 10:1 ACN/H₂O B + A B 37° C. 4 days DCM A + B A 54° C. 3days EtOH A + B A + B↓² 67° C. overnight EtOH A 67° C. 4 days EtOH B + CA³ + B 67° C. overnight EtOH A + C A 67° C. overnight EtOH ¹Duration andtemperatures are approximate. ²Downward arrow indicates the peakintensities of the associated crystalline phase have decreased relativeto those of the starting mixture. The length of time of the experimentis not sufficient to reach equilibrium; nevertheless, conclusions of thepredominant form can be made based on the resulting mixture. ³Thesolution-mediated interconversion process provides a pathway for theless soluble (more stable relative to the other) crystal to grow at theexpense of the more soluble crystal form. However, when neither of theforms involved in the binary competitive slurry is the mostthermodynamically stable form, the possibility of the most stablecrystal to grow at the expense of the other two more soluble crystalforms can also result. This solvent-mediated polymorphic transformationis controlled by its nucleation rate, which is generally higher in asolvent giving higher solubility. In addition to the solubility, thestrength of the solvent-solute interactions is also important. Degree ofagitation and temperature also change the polymorphic transformationrate by influencing the crystallization kinetics of the more stablepolymorph.

Crystalline Form B exhibits a lower apparent solubility than CrystallineForm A in both methanol and water (Table 17 below). Solution calorimetry(SolCal) analyses are also performed to determine the heats of solutionin methanol at 25° C. and confirm the stable form at this temperature(see Example 15). Based on SolCal data, the dissolutions of bothCrystalline Forms A and B in methanol are endothermic events withaverage heats of solution of 48.618 and 64.567 J/g, respectively,indicating that Crystalline Form B is more stable than Crystalline A at25° C.

Experimental: Approximate Solubility

A weighed sample is treated with aliquots of the test solvent at roomtemperature. The mixture is sonicated between additions to facilitatedissolution. Complete dissolution of the test material is determined byvisual inspection. Solubility is estimated based on the total solventused to provide complete dissolution. The actual solubility may begreater than the value calculated because of the use of solvent aliquotsthat are too large or due to a slow rate of dissolution.

TABLE 17 Approximate Solubility of Crystalline Forms A and B CrystallineForm Solvent Solubility (mg/mL) A MeOH 74 B MeOH 63 A H₂O  34¹ B H₂O 21² ¹Nucleation observed after one day. A single crystal of CrystallineForm B is isolated. ²Nucleation of irregular fines with no birefringenceobserved after 7 days.

Example 11—Accelerated Stress Conditions

Crystalline Forms A, B, and C are exposed to accelerated stressconditions for two weeks (Table 18 below). Based on XRPD, CrystallineForms A and B remain unchanged at 30° C./56% RH or 40° C./75% RH withinthe time frame evaluated. However, Crystalline Form C converts to amixture of Crystalline Forms A and B within two weeks at 40° C./75% RH.Crystalline Form C is metastable at this condition. For Crystalline FormA, in the absence of seeds of the more stable polymorph, the criticalfree energy barrier for the nucleation of Crystalline Form B is notovercome in the solid state or in solvent mediated form conversionexperiments within the time frame evaluated.

TABLE 18 Accelerated Stability Evaluation of Crystalline Form Results(Crystalline Crystalline Form Condition Time Form) A source sample — Asubsample stored in freezer T zero — 30° C./60% RH 2 weeks A 40° C./75%RH 2 weeks A B source sample — B subsample stored in freezer T zero —30° C./60% RH 2 weeks B 40° C./75% RH 2 weeks B C source sample — Csubsample stored in freezer T zero — 40° C./75% RH 2 weeks A + B

T_(t,B→A) is between 37 and 54° C. A mixture of Forms A and B(combination of portions 1 and 2 from Example 17), completely convertsto Form A upon exposure to 230° C. (Table 19 below).

Experimental: Relative Humidity Stress

The following relative humidity jars (saturated salt solutions are usedto generate desired relative humidity) are utilized: 75% RH (NaCl) and56% RH (NaBr) (Nyqvist, H., Int. J. Pharm. Tech. &Prod. Mfr. 1983, 4(2), 47-48).

TABLE 19 Physical Stability of Mixture of Forms A and B Method¹Observation² Results expose to 230° C., sublimation is observed; A moistpH paper held in head space no pH change is noted, above samplesuggesting no loss of HCl upon heating; fines and large blades, B ¹Timeand temperature are approximate. ²B = birefringent when observed bypolarized light microscopy ³Upward arrow indicates the peak intensitiesof the associated crystalline phase have increased relative to those ofthe starting mixture.

Example 12—Preparation of Crystalline Form B

A portion of Crystalline Form A from Example 5 above is slurried withwater at ambient temperature for 16 days. Crystalline Form B isisolated. An XRPD of the product is in FIG. 48. The XRPD pattern iscollected with a PANalytical X'Pert PRO MPD diffractometer using anincident beam of Cu radiation produced using an Optix long, fine-focussource. An elliptically graded multilayer mirror is used to focus Cu KαX-rays through the specimen and onto the detector. Prior to theanalysis, a silicon specimen (NIST SRM 640e) is analyzed to verify theobserved position of the Si 111 peak is consistent with theNIST-certified position. A specimen of the sample is sandwiched between3-μm-thick films and analyzed in transmission geometry. A beam-stop,short antiscatter extension, and an antiscatter knife edge are used tominimize the background generated by air. Soller slits for the incidentand diffracted beams are used to minimize broadening from axialdivergence. Diffraction patterns are collected using a scanningposition-sensitive detector (X'Celerator) located 240 mm from thespecimen and Data Collector software v. 2.2b. Data acquisitionparameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-ray Tube: Cu(1.54059 Å), Voltage: 45 kV, Amperage: 40 mA, Scan Range: 1.00-39.99°2θ, Step Size: 0.017 °2θ, Collection Time: 716 s, Scan Speed:3.3°/min., Slit: DS: ½°, SS: null, Revolution Time: 1.0 s, Mode:Transmission.

Example 13—XRPD of Mixture of Crystalline Form A and Minor Quantity ofCrystalline Form B

An XRPD pattern of a mixture of Crystalline Form A and a minor quanitityof Crystalline Form B product is in FIG. 49 (Example 17 for synthesis).The XRPD pattern is collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu radiation produced using anOptix long, fine-focus source. An elliptically graded multilayer mirroris used to focus Cu Kα X-rays through the specimen and onto thedetector. Prior to the analysis, a silicon specimen (NIST SRM 640e) isanalyzed to verify the observed position of the Si 111 peak isconsistent with the NIST-certified position. A specimen of the sample issandwiched between 3-μm-thick films and analyzed in transmissiongeometry. A beam-stop, short antiscatter extension, and an antiscatterknife edge are used to minimize the background generated by air. Sollerslits for the incident and diffracted beams are used to minimizebroadening from axial divergence. Diffraction patterns are collectedusing a scanning position-sensitive detector (X'Celerator) located 240mm from the specimen and Data Collector software v. 2.2b. Dataacquisition parameters are: Panalytical X-Pert Pro MPD PW3040 Pro, X-rayTube: Cu (1.54059 Å), Voltage: 45 kV, Amperage: 40 mA, Scan Range:1.00-39.99 °2θ, Step Size: 0.017 °2θ, Collection Time: 720 s, ScanSpeed: 3.2°/min., Slit: DS: ½°, SS: null, Revolution Time: 1.0 s, Mode:Transmission.

Example 14—Solution Calorimetry (SolCal) Analyses of Crystalline Forms Aand B

Solution calorimetry analysis for each form is measured in triplicate inmethanol and the data are summarized in Table 21. For each test, twoheats of solution are obtained—one calculated using a calibrationpreceding the sample analysis and one calculated using a calibrationfollowing the sample analysis. The mean values from the two calibrationsare also provided in the table. Clear solutions are observed after eachtest.

The dissolutions of both Crystalline Forms A and B in methanol areendothermic events with average heats of solution are 48.618 and 64.567J/g, respectively. The standard deviation for each set is 0.457 and0.344 J/g, respectively.

Crystalline Form B has a higher heat of solution value than Form A,indicating Crystalline Form B is more stable than A at 25° C. Theenthalpy of the transition calculated from the SolCal data from Form Bto Form A is about 15.9 J/g. The difference in the heat of fusion in thesolid-state transition in the DSC of Crystalline Form B is 15.9 J/g (seeFIGS. 8 and 55), which is in good agreement with the SolCal results.

Solution calorimetry is performed using a Thermometric 2225 PrecisionSolution Calorimeter, a semi-adiabatic calorimeter. Solution CalorimeterSystem v.1.2 software is used. Samples are weighed into glass crushingampoules and are sealed using silicone rubber plugs and hot wax.Experiments are carried out in 100 mL of methanol at 25° C. Themeasurement of the heats of solution of the samples is both preceded andfollowed by calibrations using an internal heater. The heats of solutionare calculated using dynamic of calibration model.

TABLE 21 Heats of Solution of Crystalline Forms A and B in Methanol Ob-ΔH₁, ΔH₂, ΔH_(mean), serva- Sample Replicate J/g^((a)) J/g^((b)) J/gtion^((c)) Crystal- 1 (52.540 mg Crystalline 46.050 50.168 48.109 clearline Form A, stirrer 500 rpm) solution Form A 2 (55.427 mg Crystalline48.293 49.217 48.755 clear Form A, stirrer 500 rpm) solution 3 (49.393mg Crystalline 48.077 49.905 48.991 clear Form A, stirrer 500 rpm)solution average, J/g 48.618 — standard deviation 0.457 — Crystal- 1(56.730 mg Crystalline 64.004 64.985 64.495 clear line Form A, stirrer500 rpm) solution Form B 2 (49.276 mg Crystalline 63.471 65.057 64.264clear Form A, stirrer 500 rpm) solution 3 (51.723 mg Crystalline 64.46165.421 64.941 clear Form A, stirrer 500 rpm) solution average, J/g64.567 — standard deviation 0.344 — ^((a))Calculated using thecalibration before breaking the sample vial. ^((b))Calculated using thecalibration after breaking the sample vial. ^((c))Observations are madeat the time when tests are completed.

Example 15—Hot Stage Microscropy (HSM) of Crystalline Form A fromExample 1

Hot stage microscopy is performed using a Linkam hot stage (model FTIR600) mounted on a Leica DM LP microscope. Samples are observed using a20× objective (obj.). Samples are placed on a coverslip, and a secondcoverslip is then placed over the sample. Each sample is visuallyobserved as the stage is heated. Images are captured using a SPOTInsight™ color digital camera with SPOT Software v. 4.5.9. The hot stageis calibrated using USP melting point standards.

By HSM of Crystalline Form A, between 182 and 239° C., the smallestparticles evaporate and the resulting vapor recrystallizes into largercrystals. Condensation and melt are observed between 239 and 247° C.;the needles appear to melt last consistent with the multiple endothermsobserved by DSC. Two preparations are utilized for the analysis. For thefirst, discoloration (decomposition) is observed after melt. For thesecond, rapid cooling results in recrystallization of the melt.

Example 16—Preparation of Mixture of Crystalline Forms A and B

Commercially available reagents are used as received unless otherwisenoted. Reactions requiring inert atmospheres are run under nitrogenunless otherwise noted.

MW d Compound (g/mol) (g/mL) Equivalents Amt/mol Reaction2-naphthylacetonitrile 167.21 NA 1.0 mol eq 50 Kg/299.03 mol (SM)(S)-(+)-epichlorohydrin 92.52 3.12 1.12 mol eq 31.0 Kg/334.9 moltetrahydrofuran 72.11 0.889 5.0 ml/g SM 250 L 2M sodiumbis(trimethylsilyl)amide  2.0M 0.916 2 mol eq 299 L/598.0 mol in THFborane-dimethylsulfide 10.0M 0.80 2.5 mol eq 89.7 L/897.0 mol Isolation2M HCl (aqueous)   2M NA 11.5 ml/g SM 650 L isopropyl acetate 102.130.872 4 mL/g SM as required water 18.02 1.00 5 mL/g SM as requiredammonia (aqueous) NA 0.889 2.0 mL/g SM 100 L methylene chloride 60 1.3254 × 5 mL/g as required SM 2-methyltetrahydrofuran 86.13 0.86 12.6 mL/gSM as required para-toluenesulfonic acid 190.22 NA 0.953 mol eq. 54.2Kg/284.9 mol monohydrate

Steps 1 and 2

2-naphthylacetonitrile (50 Kg) is dissolved in THF (250 L), 32 kg of(S)-(+)-epichlorohydrin is added and the solution cooled to −10° C. A2.0 M solution of sodium hexamethyldisilylazane in THF (299 L) is thenadded keeping the internal temperature below −10° C. This additionrequires 14 hrs., 14 minutes to complete. The reaction mixture is thenstirred an additional four hours at approximately −10° C., after which asample of the reaction mixture is analyzed by HPLC. While keeping theinternal temperature less than 0° C., borane dimethylsulfide (71 kg) isadded over four hours and 33 minutes. After completion of the boraneaddition the reaction mixture is slowly heated to 60° C. to reduce thenitrile to the amine. During this heat-up, an exotherm is noted, whichinitiates at 45° C. After heating at 60° C. for 14 hours and 46 minutes,a sample of the reaction mixture is analyzed by HPLC.

The reaction mixture is then cooled to 24° C. and transferred to asolution of 2M HCl over 2 hours and 28 minutes and the reactor is rinsedwith THF (22.3 Kg) and transferred to the HCl containing reactionmixture. The two phase mixture is heated to 45° C. to 55° C. and stirredfor 1 hour 48 minutes at this temperature followed by cooling to 30° C.The pH of the quenched reaction mixture is measured and found to be 1.Reaction workup continues by addition of IPAc, stir, and separate thelayers. Charge 1 M HCl solution to the organic layer, stir, separate thelayers, and discard the organic layer. Aqueous ammonia is added to thecombined aqueous layer and the pH measured which shows a pH of 9. Workupthen continues by extraction with two extractions of the aqueous layerwith IPAc. The combined organic extracts are then washed with 5% sodiumchloride solution. The resulting organic layer is partially concentratedto azeotropically dry and co-evaporation with methylene chloride fourtimes and followed by dilution with methylene chloride and transfer ofthe reaction mixture via in-line filter to clean, dry reactor anddiluting with IPAc. p-Toluenesulfonic acid hydrate (54 Kg) is then addedin portions to precipitate the desired product as its pTsOH salt and thereaction suspension is stirred over three hours at 10° C. to 15° C. andthe product is isolated by filtration. The filter cake is washed with2-methyltetrahydrofuran and followed by IPAc then pull dried over twohours. The crude product is purified by stirring with2-methyltetrahydrofuran over 11 hours 36 minutes at 10° C. to 15° C. andthe product is isolated by filtration. The filtered solid is washed with2-methyltetrahydrofuran and then dried to a constant weight to give 73.8Kg of the desired product as a white solid. Yield=73.8 Kg (62%).HPLC=96.8%.

Steps 3 and 4

MW d Compound (g/mol) (g/mL) Equivalents Amt/mol Reaction2-naphthylcyclopropylamine-tosylate 399.51 NA 1.0 mol eq 73.8 Kg/184.7mol salt 2-methyltetrahydrofuran 86.13 0.86 10 mL/g as required SMisopropylacetate 102.13 0.872 as required as required thionyl chloride118.97 1.638 1.2 eq 26.4 Kg/221.9 mol sodium hydroxide, 50% aqueous 401.548 11 mol eq 165.3 Kg Isolation water 18.02 1.00 10 mL/g as requiredSM magnesium sulfate NA NA 0.5 g/g 36.5 Kg hydrogen chloride inisopropyl alcohol 5.7M NA 1.0 mol eq 33.6 L Ethyl alcohol 200 (SpecialIndustrial 80.25 0.786 14 mL/g as required denatured) SM

The amine-pTsOH salt (73.8 Kg) obtained from step 2 above is suspendedin 2-methyltetrahydrofuran (738 L) to give a slurry. Thionyl chloride(26.4 kg) is then added over three hours. Upon completion of the thionylchloride addition, the reaction mixture is stirred three additionalhours. Aqueous sodium hydroxide (5M, 10 mol equivalents) is added overthree hours followed by two hours of additional stirring. The layers areallowed to settle and the pH of the aqueous layer is checked and foundto be 9. Water (2 mL/g, SM) is added, the reaction mixture is stirred 15more minutes at room temperature, and the layers are separated and theorganic layer washed twice with water. The aqueous layers are combinedand back extracted with 2-methyltetrahydrofuran and the initial organiclayer and the back extract combined. These combined organic layers arewashed with brine, dried over magnesium sulfate, and partiallyconcentrated. After concentration, hydrogen chloride in IPA (1.0 molequivalent of HCl in IPA) is added and stirred 2 hours to form the crudesalt which is isolated by filtration, washed with2-methyltetrahydrofuran and followed by IPAc and then pull dried over 2hours under vacuum.

The crude product (82.6 Kg) obtained from above is dissolved in 14volumes of hot ethanol (70° C.) and then filtered via an encapsulatedcarbon filter to improve the color. The dissolution vessel and theencapsulated carbon filter and transfer line are then rinsed withadditional hot ethanol (70° C.) and the rinse combined with thefiltrate. The combined filtrate and washes are partially concentrated invacuo to approximately 5 total volumes (relative to crude product input)and then stirred over two hours at 0° C. The resulting solids areisolated by filtration, the filter cake washed with cooled (0° C. to 5°C.) ethanol and followed by IPAc and the washed solids then dried togive 33.6 Kg of the product as a slightly off-white solid. Yield=33.6 Kg(73% yield). Achiral HPLC=98%.

The material is then dried via cone drying. After drying, the materialis sieved.

A portion of the material (14 Kg) is then dissolved in 15 volumes of hotethanol (70° C.) and filtered via an encapsulated carbon filter toimprove the color. The dissolution vessel and the encapsulated carbonfilter and transfer line are then rinsed with additional hot ethanol(70° C.) and the rinse combined with the filtrate. The combined filtrateand washes are partially concentrated in vacuo to approximately 8 totalvolumes (relative to starting 14 Kg of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochlorideinput) and then stirred over two hours at 18° C. The resulting solidsare isolated by filtration, the filter cake washed with cooled (5° C. to10° C.) ethanol and followed by IPAc and the washed solids then dried togive 9.4 Kg (67.1% of yield) of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride as awhite solid. Achiral HPLC=98%.

An XRPD of the product is shown in FIG. 56. The XRPD is consistent withCrystalline Form A with evidence of lower intensity peaks at 18.90,19.2°, 23.6°, 23.8°, 28.2°, and 28.7° 20 attributed to Crystalline FormB. The XRPD pattern is collected with a PANalytical X'Pert PRO MPDdiffractometer using an incident beam of Cu radiation produced using anOptix long, fine-focus source. An elliptically graded multilayer mirroris used to focus Cu Kα X-rays through the specimen and onto thedetector. Prior to the analysis, a silicon specimen (NIST SRM 640e) isanalyzed to verify the observed position of the Si 111 peak isconsistent with the NIST-certified position. A specimen of the sample issandwiched between 3-m-thick films and analyzed in transmissiongeometry. A beam-stop, short antiscatter extension, antiscatter knifeedge, are used to minimize the background generated by air. Soller slitsfor the incident and diffracted beams are used to minimize broadeningfrom axial divergence. Diffraction patterns are collected using ascanning position-sensitive detector (X'Celerator) located 240 mm fromthe specimen and Data Collector software v. 2.2b.

XRPD Data acquisition parameters are: Panalytical X-Pert Pro MPD PW3040Pro, X-ray Tube: Cu (1.54059 Å), Voltage: 45 kV, Amperage: 40 mA, ScanRange: 1.00-39.99 °2θ, Step Size: 0.017 °2θ, Collection Time: 721 s,Scan Speed: 3.2°/min., Slit: DS: ½°, SS: null, Revolution Time: 1.0 s,Mode: Transmission.

Example 17—Preparation of Mixture of Crystalline Forms A and B

To a 2 L 3 neck round bottom flask with mechanical stirring, refluxcondenser, nitrogen inlet, thermocouple, and heating mantle, is added 50g of the product from Example 16 above and EtOH Special Industrial (750mL, 15 vol). The mixture is heated to reflux (77° C.). Solids dissolveforming clear solution at 72° C. Loose charcoal slurry is added (5 g,0.1 eq in 100 mL EtOH) and the mixture is stirred for 1 hour. Filter andrinse with hot EtOH (150 mL). Split filtrate into two equal portions.

Portion 1

Concentrate down to 10 vol (250 mL) at 50° C. Small amount of solidsstart to precipitate during concentration. Transfer to 500 mL 3 neckround bottom flask with mechanical stirring and allow to cool to roomtemp. Stir for 2 hours at room temp. Suspension forms. Filter and rinsewith EtOH (50 mL, 2 vol) followed by IPAc (50 mL). Pull dry on filter.Yield=20.5 g (82%).

Portion 2

Concentrate down to 7 vol (175 mL) at 50° C. Small amount of solidsstart to precipitate during concentration. Transfer to 500 mL 3 neckround bottom flask with mechanical stirring and allow to cool to roomtemp. Stir for 2 hours at room temp. Suspension forms. Filter and rinsewith EtOH (50 mL, 2 vol) followed by IPAc (50 mL). Pull dry on filter.Yield=19.8 g (79.2%).

Product from the two portions are combined and an XRPD pattern of thecombined portions is in FIG. 49 (Example 13).

Example 18—Preparation of Crystalline Forms

Crystalline Form A from Example 5 is used to make the followingcrystalline forms.

Solvent Method^(a) Observation^(b) Results IPA 1. saturated solution, 1.— A + C ambient 2. fine irregular, B 2. cooled in freezer 1. saturatedsolution, 1. — B + C ambient 2. fines, B 2. cooled in freezer ^(a)Timeand temperature are approximate. ^(b)B = birefringent when observed bypolarized light microscopy.

The invention claimed is:
 1. Crystalline Form A of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride,wherein the Crystalline Form A exhibits an X-ray powder diffraction(XRPD) pattern comprising at least three 2-theta (°) values selectedfrom the group consisting of 6.87±0.20, 12.26±0.20, 13.78±0.20,14.49±0.20, 15.42±0.20, 16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20,19.45±0.20, 20.06±0.20, 20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20,22.90±0.20, 24.69±0.20, 25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20,27.52±0.20, and 27.76±0.20, wherein the XRPD is measured using anincident beam of Cu radiation.
 2. The Crystalline Form A of claim 1,wherein the Crystalline Form A exhibits an X-ray powder diffraction(XRPD) pattern comprising at least five 2-theta (°) values selected fromthe group consisting of 6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20,15.42±0.20, 16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20,20.06±0.20, 20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20,24.69±0.20, 25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20,and 27.76±0.20, wherein the XRPD is measured using an incident beam ofCu Kα radiation.
 3. The Crystalline Form A of claim 2, wherein theCrystalline Form A exhibits an X-ray powder diffraction (XRPD) patterncomprising at least nine 2-theta (°) values selected from the groupconsisting of 6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20,16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20,20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20,25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20, and27.76±0.20, wherein the XRPD is measured using an incident beam of Cu Kαradiation.
 4. The Crystalline Form A of claim 3, wherein the CrystallineForm A exhibits an X-ray powder diffraction (XRPD) pattern comprising atleast ten 2-theta (°) values selected from the group consisting of6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20, 16.55±0.20,17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20, 20.46±0.20,20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20, 25.17±0.20,25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20, and 27.76±0.20, whereinthe XRPD is measured using an incident beam of Cu Kα radiation.
 5. TheCrystalline Form A of claim 4, wherein the Crystalline Form A exhibitsan X-ray powder diffraction (XRPD) pattern comprising at least twelve2-theta (°) values selected from the group consisting of 6.87±0.20,12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20, 16.55±0.20, 17.15±0.20,18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20, 20.46±0.20, 20.68±0.20,20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20, 25.17±0.20, 25.44±0.20,25.69±0.20, 26.36±0.20, 27.52±0.20, and 27.76±0.20, wherein the XRPD ismeasured using an incident beam of Cu Kα radiation having a wavelengthof 1.54059 Å.
 6. The Crystalline Form A of claim 5, wherein theCrystalline Form A exhibits an X-ray powder diffraction (XRPD) patterncomprising at least fifteen 2-theta (°) values selected from the groupconsisting of 6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20,16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20,20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20,25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20, and27.76±0.20, wherein the XRPD is measured using an incident beam of Cu Kαradiation having a wavelength of 1.54059 Å.
 7. The Crystalline Form A ofclaim 6, wherein the Crystalline Form A exhibits an X-ray powderdiffraction (XRPD) pattern comprising at least twenty 2-theta (°) valuesselected from the group consisting of 6.87±0.20, 12.26±0.20, 13.78±0.20,14.49±0.20, 15.42±0.20, 16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20,19.45±0.20, 20.06±0.20, 20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20,22.90±0.20, 24.69±0.20, 25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20,27.52±0.20, and 27.76±0.20, wherein the XRPD is measured using anincident beam of Cu Kα radiation having a wavelength of 1.54059 Å. 8.The Crystalline Form A of claim 1, wherein the Crystalline Form Acomprises less than 5 wt. % of any other crystalline form of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. 9.The Crystalline Form A of claim 3, wherein the Crystalline Form Acomprises less than 5 wt. % of any other crystalline form of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. 10.The Crystalline Form A of claim 3, wherein the Crystalline Form Acomprises less than 2 wt. % of any other crystalline form of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. 11.The Crystalline Form A of claim 3, wherein the Crystalline Form Acomprises less than 1 wt. % of any other crystalline form of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. 12.The Crystalline Form A of claim 5, wherein the Crystalline Form Acomprises less than 1 wt. % of any other crystalline form of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. 13.The Crystalline Form A of claim 3, wherein the Crystalline Form Acomprises less than 0.1 wt. % of any other crystalline form of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride. 14.A pharmaceutical composition comprising Crystalline Form A of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride anda pharmaceutically acceptable diluent or carrier, wherein theCrystalline Form A exhibits an X-ray powder diffraction (XRPD) patterncomprising at least three 2-theta (°) values selected from the groupconsisting of 6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20,16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20,20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20,25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20, and27.76±0.20, wherein the XRPD is measured using an incident beam of Curadiation.
 15. The pharmaceutical composition of claim 14, wherein theCrystalline Form A exhibits an X-ray powder diffraction (XRPD) patterncomprising at least nine 2-theta (°) values selected from the groupconsisting of 6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20,16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20,20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20,25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20, and27.76±0.20, wherein the XRPD is measured using an incident beam of Cu Kαradiation.
 16. The pharmaceutical composition of claim 15, wherein theCrystalline Form A exhibits an X-ray powder diffraction (XRPD) patterncomprising at least twelve 2-theta (°) values selected from the groupconsisting of 6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20,16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20,20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20,25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20, and27.76±0.20, wherein the XRPD is measured using an incident beam of Cu Kαradiation having a wavelength of 1.54059 Å.
 17. The pharmaceuticalcomposition of claim 14, wherein the pharmaceutical composition is anoral sustained release pharmaceutical composition.
 18. Thepharmaceutical composition of claim 15, wherein the pharmaceuticalcomposition is an oral sustained release pharmaceutical composition. 19.The pharmaceutical composition of claim 16, wherein the pharmaceuticalcomposition is an oral sustained release pharmaceutical composition. 20.A method for treatment of attention deficit hyperactivity disorder in apatient in need thereof, wherein the method comprises administering tothe patient Crystalline Form A of(1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride,wherein the Crystalline Form A exhibits an X-ray powder diffraction(XRPD) pattern comprising at least three 2-theta (°) values selectedfrom the group consisting of 6.87±0.20, 12.26±0.20, 13.78±0.20,14.49±0.20, 15.42±0.20, 16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20,19.45±0.20, 20.06±0.20, 20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20,22.90±0.20, 24.69±0.20, 25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20,27.52±0.20, and 27.76±0.20, wherein the XRPD is measured using anincident beam of Cu radiation.
 21. The method of claim 20, wherein theCrystalline Form A exhibits an X-ray powder diffraction (XRPD) patterncomprising at least nine 2-theta (°) values selected from the groupconsisting of 6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20,16.55±0.20, 17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20,20.46±0.20, 20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20,25.17±0.20, 25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20, and27.76±0.20, wherein the XRPD is measured using an incident beam of Cu Kαradiation.
 22. The method of claim 21, wherein the Crystalline Form Aexhibits an X-ray powder diffraction (XRPD) pattern comprising at leasttwelve 2-theta (°) values selected from the group consisting of6.87±0.20, 12.26±0.20, 13.78±0.20, 14.49±0.20, 15.42±0.20, 16.55±0.20,17.15±0.20, 18.19±0.20, 18.50±0.20, 19.45±0.20, 20.06±0.20, 20.46±0.20,20.68±0.20, 20.96±0.20, 21.54±0.20, 22.90±0.20, 24.69±0.20, 25.17±0.20,25.44±0.20, 25.69±0.20, 26.36±0.20, 27.52±0.20, and 27.76±0.20, whereinthe XRPD is measured using an incident beam of Cu Kα radiation having awavelength of 1.54059 Å.
 23. A method of treatment of attention deficithyperactivity disorder, a fragile X-associated disorder, autism spectrumdisorder, or a substance abuse disorder in a patient in need thereof,wherein the method comprises administering to the patient thepharmaceutical composition of claim
 14. 24. A method of treatment ofattention deficit hyperactivity disorder in a patient in need thereof,wherein the method comprises administering to the patient thepharmaceutical composition of claim
 17. 25. A method of treatment ofattention deficit hyperactivity disorder in a patient in need thereof,wherein the method comprises administering to the patient thepharmaceutical composition of claim
 18. 26. A method of treatment ofattention deficit hyperactivity disorder in a patient in need thereof,wherein the method comprises administering to the patient thepharmaceutical composition of claim 19.